Publications by authors named "Ravindra Uppaluri"

67 Publications

Tumor-associated neutrophils (TANs) in human carcinoma-draining lymph nodes: a novel TAN compartment.

Clin Transl Immunology 2021 16;10(2):e1252. Epub 2021 Feb 16.

Section of Pathology Department of Molecular and Translational Medicine University of Brescia Brescia Italy.

Objectives: The role of tumor-associated neutrophils (TANs) in the nodal spread of cancer cells remains unexplored. The present study evaluates the occurrence and clinical significance of human nodal TANs.

Methods: The relevance, derivation, phenotype and interactions of nodal TANs were explored a large immunohistochemical analysis of carcinoma-draining lymph nodes, and their clinical significance was evaluated on a retrospective cohort of oral squamous cell carcinomas (OSCC). The tumor-promoting function of nodal TAN was probed in the OSCC TCGA dataset combining TAN and epithelial-to-mesenchymal transition (EMT) signatures.

Results: The pan-carcinoma screening identified a consistent infiltration (59%) of CD66b  TANs in tumor-draining lymph nodes (TDLNs). Microscopic findings, including the occurrence of intra-lymphatic conjugates of TANs and cancer cells, indicate that TANs migrate through lymphatic vessels. experiments revealed that OSCC cell lines sustain neutrophil viability and activation via release of GM-CSF. Moreover, by retrospective analysis, a high CD66b TAN density in M-TDLNs of OSCC ( = 182 patients) predicted a worse prognosis. The analysis of the OSCC-TCGA dataset unveiled that the expression of a set of neutrophil-specific genes in the primary tumor (PT) is highly associated with an EMT signature, which predicts nodal spread. Accordingly, in the PT of OSCC cases, CD66bTANs co-localised with PDPNS100A9 EMT-switched tumor cells in areas of lymphangiogenesis. The pro-EMT signature is lacking in peripheral blood neutrophils from OSCC patients, suggesting tissue skewing of TANs.

Conclusion: Our findings are consistent with a novel pro-tumoral TAN compartment that may promote nodal spread EMT, through the lymphatics.
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http://dx.doi.org/10.1002/cti2.1252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886597PMC
February 2021

Yap1 Mediates Trametinib Resistance in Head and Neck Squamous Cell Carcinomas.

Clin Cancer Res 2021 Apr 5;27(8):2326-2339. Epub 2021 Feb 5.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Purpose: In a head and neck squamous cell carcinoma (HNSCC) "window of opportunity" clinical trial, we reported that trametinib reduced MEK-Erk1/2 activation and resulted in tumor responses in a subset of patients. Here, we investigated resistance to trametinib and molecular correlates in HNSCC cell lines and patient samples.

Experimental Design: HNSCC cell lines were treated with trametinib to generate resistant lines. Candidate bypass pathways were assessed using immunoblotting, CRISPR knockout, and survival assays. Effectiveness of combined trametinib and verteporfin targeting was evaluated. Patient-derived xenografts (PDXs) from responder patients were treated with trametinib and resistant tumors were analyzed. Window trial clinical samples were subjected to whole-exome and RNA sequencing.

Results: HNSCC cell lines developed resistance (CAL27-TR and HSC3-TR) after prolonged trametinib exposure. Downstream effectors of the Hippo pathway were activated in CAL27-TR and HSC3-TR, and combined trametinib and verteporfin treatment resulted in synergistic treatment response. We defined the Hippo pathway effector Yap1 as an induced survival pathway promoting resistance to trametinib in HSC3-TR. Yap1 was necessary for HSC3-TR trametinib resistance, and constitutively active Yap1 was sufficient to confer resistance in parental HSC3. Analysis of trametinib neoadjuvant trial patient tumors indicated canonical MEK-Erk1/2 pathway activating mutations were infrequent, and Yap1 activity increased following trametinib treatment. Trametinib treatment of a PDX from a responder patient resulted in evolution of resistance with increased Yap1 expression and activity.

Conclusions: These studies identify a Yap1-dependent resistance to trametinib therapy in HNSCCs. Combined Yap1 and MEK targeting may represent a strategy to enhance HNSCC response.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-4179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8046740PMC
April 2021

Epigenetic modulation of immunotherapy and implications in head and neck cancer.

Cancer Metastasis Rev 2021 Mar 5;40(1):141-152. Epub 2021 Jan 5.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Cancer progression is facilitated by distinct mechanisms developed by cancer cells to avoid immune recognition and clearance. The clinical application of immune checkpoint blockade (ICB), via monoclonal antibodies blocking PD-1/PD-L1 and CTLA4, has achieved promising durable therapeutic response in various cancer types, including recurrent and metastatic head and neck squamous cell carcinomas (HNSCC). HNSCC represents a rational target of ICB treatment given its relatively high mutation burden and the presence of immune infiltrates. However, the limited response rates and recent negative clinical trials data identify an urgent need for new strategies to overcome immunotherapy resistance. Preclinical studies have revealed an important contribution of epigenetic regulators in the anti-tumor immune response. Multiple components of the tumor and host immune system interaction are under epigenetic regulation, including the cancer cells themselves, cytotoxic T lymphocytes, regulatory T lymphocytes, natural killer cells, and tumor-associated macrophages. Epigenetic targeting drugs such as DNA methyltransferase inhibitors, histone deacetylase, and methyltransferase inhibitors have demonstrated the potential to reverse immune suppression in various cancer models. The aim of this review is to summarize recent preclinical studies focused on investigating the function of epigenetic modulation in the host immune and cancer cell interface. We also provide a perspective on combining epigenetic modulation and immunotherapy in the management of HNSCC to improve outcomes-an area of great interest in future clinical studies.
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http://dx.doi.org/10.1007/s10555-020-09944-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897200PMC
March 2021

Personalized cancer vaccination in head and neck cancer.

Cancer Sci 2021 Mar 27;112(3):978-988. Epub 2021 Jan 27.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Cancer is characterized by an accumulation of somatic mutations that represent a source of neoantigens for targeting by antigen-specific T cells. Head and neck squamous cell carcinoma (HNSCC) has a relatively high mutation burden across all cancer types, and cellular immunity to neoantigens likely plays a key role in HNSCC clinical outcomes. Immune checkpoint inhibitors (CPIs) have brought new treatment options and hopes to patients with recurrent and/or metastatic HNSCC. However, many patients do not benefit from CPI therapies, highlighting the need for novel immunotherapy or combinatorial strategies. One such approach is personalized cancer vaccination targeting tumor-associated antigens and tumor-specific antigens, either as single agents or in combination with other therapies. Recent advances in next-generation genomic sequencing technologies and computational algorithms have enabled efficient identification of somatic mutation-derived neoantigens and are anticipated to facilitate the development of cancer vaccine strategies. Here, we review cancer vaccine approaches against HNSCC, including fundamental mechanisms of a cancer vaccine, considerations for selecting appropriate antigens, and combination therapies.
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http://dx.doi.org/10.1111/cas.14784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935792PMC
March 2021

Clinical Decision-making About Neoadjuvant Nivolumab Plus Ipilimumab-Reply.

JAMA Oncol 2021 Feb;7(2):309-310

Brigham and Women's Hospital, Boston, Massachusetts.

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http://dx.doi.org/10.1001/jamaoncol.2020.6994DOI Listing
February 2021

Hospitalization rates and 30-day all-cause mortality among head and neck cancer patients and survivors with COVID-19.

Oral Oncol 2021 01 6;112:105087. Epub 2020 Nov 6.

Dana-Farber Cancer Institute, Center for Head & Neck Oncology, Boston, MA; Department of Surgery, Division of Otolaryngology-Head & Neck Surgery, Brigham & Women's Hospital, Boston, MA.

Background: The impact of COVID-19 on patients with cancer is emerging, but data are urgently needed for head and neck cancer (HNC) patients or survivors who are inherently high-risk for severe illness and mortality with SARS-CoV-2 infection.

Methods: This multi-institution, academic cohort study collected comprehensive data on clinical risk factors, COVID-19 symptoms and viral testing patterns, information about hospitalization rates, and predictors of survival among HNC patients with active disease or in remission. The primary endpoint was 30-day all-cause mortality from the date of confirmed COVID-19. We performed multivariate analysis to understand the prognostic value of clinical and laboratory parameters on outcomes.

Results: Thirty-two patients with COVID-19 and HNC were included. Median age was 70 (range: 38-91) with 38% aged 75+, and 34% resided in long-term care facilities (LTCF). Thirteen (41%) had active cancer, with 6 (19%) on cancer therapy within 4 weeks of COVID-19 diagnosis. New or worsening cough and fatigue were the most commonly reported presenting symptoms. More than 30% required >1 SARS-CoV-2 test before confirming a positive result. Twenty (63%) required hospitalization. At data cutoff, 7 (22%) had died (1 on active cancer treatment), with a 30-day all-cause mortality of 18.9% (95%CI: 11.4-33.6) among all patients, and 71.5% (95%CI: 38.2-92.3) among those requiring intensive care unit (ICU) admission. ICU admission and residing in a LTCF predicted worse outcomes (p < 0.01), while age, gender, and recent treatment did not.

Conclusions: We observed high 30-day all-cause mortality among HNC patients with COVID-19, but most were not on active cancer therapy.
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http://dx.doi.org/10.1016/j.oraloncology.2020.105087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833708PMC
January 2021

Neoadjuvant Nivolumab or Nivolumab Plus Ipilimumab in Untreated Oral Cavity Squamous Cell Carcinoma: A Phase 2 Open-Label Randomized Clinical Trial.

JAMA Oncol 2020 10;6(10):1563-1570

Brigham and Women's Hospital, Boston, Massachusetts.

Importance: Novel approaches are needed to improve outcomes in patients with squamous cell carcinoma of the oral cavity. Neoadjuvant immunotherapy given prior to surgery and combining programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) immune checkpoint inhibitors are 2 strategies to enhance antitumor immune responses that could be of benefit.

Design, Setting, And Participants: In this randomized phase 2 clinical trial conducted at 1 academic center, 29 patients with untreated squamous cell carcinoma of the oral cavity (≥T2, or clinically node positive) were enrolled between 2016 to 2019.

Interventions: Treatment was administered with nivolumab, 3 mg/kg, weeks 1 and 3, or nivolumab and ipilimumab (ipilimumab, 1 mg/kg, given week 1 only). Patients had surgery 3 to 7 days following cycle 2.

Main Outcomes And Measures: Safety and volumetric response determined using bidirectional measurements. Secondary end points included pathologic and objective response, progression-free survival (PFS), and overall survival. Multiplex immunofluorescence was used to evaluate primary tumor immune markers.

Results: Fourteen patients were randomized to nivolumab (N) and 15 patients to nivolumab/ipilimumab (N+I) (mean [SD] age, 62 [12] years; 18 men [62%] and 11 women [38%]). The most common subsite was oral tongue (n = 16). Baseline clinical staging included patients with T2 (n = 20) or greater (n = 9) T stage and 17 patients (59%) with node-positive disease. Median time from cycle 1 to surgery was 19 days (range, 7-21 days); there were no surgical delays. There were toxic effects at least possibly related to study treatment in 21 patients, including grade 3 to 4 events in 2 (N), and 5 (N+I) patients. One patient died of conditions thought unrelated to study treatment (postoperative flap failure, stroke). There was evidence of response in both the N and N+I arms (volumetric response 50%, 53%; pathologic downstaging 53%, 69%; RECIST response 13%, 38%; and pathologic response 54%, 73%, respectively). Four patients had major/complete pathologic response greater than 90% (N, n = 1; N+I, n = 3). With 14.2 months median follow-up, 1-year progression-free survival was 85% and overall survival was 89%.

Conclusions And Relevance: Treatment with N and N+I was feasible prior to surgical resection. We observed promising rates of response in both arms, supporting further neoadjuvant studies with these agents.

Trial Registration: ClinicalTrials.gov Identifier: NCT02919683.
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http://dx.doi.org/10.1001/jamaoncol.2020.2955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7453348PMC
October 2020

Neoadjuvant and Adjuvant Pembrolizumab in Resectable Locally Advanced, Human Papillomavirus-Unrelated Head and Neck Cancer: A Multicenter, Phase II Trial.

Clin Cancer Res 2020 Oct 14;26(19):5140-5152. Epub 2020 Jul 14.

Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts.

Purpose: Pembrolizumab improved survival in patients with recurrent or metastatic head and neck squamous-cell carcinoma (HNSCC). The aims of this study were to determine if pembrolizumab would be safe, result in pathologic tumor response (pTR), and lower the relapse rate in patients with resectable human papillomavirus (HPV)-unrelated HNSCC.

Patients And Methods: Neoadjuvant pembrolizumab (200 mg) was administered and followed 2 to 3 weeks later by surgical tumor ablation. Postoperative (chemo)radiation was planned. Patients with high-risk pathology (positive margins and/or extranodal extension) received adjuvant pembrolizumab. pTR was quantified as the proportion of the resection bed with tumor necrosis, keratinous debris, and giant cells/histiocytes: pTR-0 (<10%), pTR-1 (10%-49%), and pTR-2 (≥50%). Coprimary endpoints were pTR-2 among all patients and 1-year relapse rate in patients with high-risk pathology (historical: 35%). Correlations of baseline PD-L1 and T-cell infiltration with pTR were assessed. Tumor clonal dynamics were evaluated (ClinicalTrials.gov NCT02296684).

Results: Thirty-six patients enrolled. After neoadjuvant pembrolizumab, serious (grades 3-4) adverse events and unexpected surgical delays/complications did not occur. pTR-2 occurred in eight patients (22%), and pTR-1 in eight other patients (22%). One-year relapse rate among 18 patients with high-risk pathology was 16.7% (95% confidence interval, 3.6%-41.4%). pTR ≥10% correlated with baseline tumor PD-L1, immune infiltrate, and IFNγ activity. Matched samples showed upregulation of inhibitory checkpoints in patients with pTR-0 and confirmed clonal loss in some patients.

Conclusions: Among patients with locally advanced, HPV-unrelated HNSCC, pembrolizumab was safe, and any pathologic response was observed in 44% of patients with 0% pathologic complete responses. The 1-year relapse rate in patients with high-risk pathology was lower than historical.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547532PMC
October 2020

Recommendations for head and neck surgical oncology practice in a setting of acute severe resource constraint during the COVID-19 pandemic: an international consensus.

Lancet Oncol 2020 07 11;21(7):e350-e359. Epub 2020 Jun 11.

Department of Otolaryngology and Head and Neck Surgery, Hôpital Européen Georges-Pompidou, Assistance Publique-Hôpitaux de Paris, Université Paris Descartes, Paris, France.

The speed and scale of the global COVID-19 pandemic has resulted in unprecedented pressures on health services worldwide, requiring new methods of service delivery during the health crisis. In the setting of severe resource constraint and high risk of infection to patients and clinicians, there is an urgent need to identify consensus statements on head and neck surgical oncology practice. We completed a modified Delphi consensus process of three rounds with 40 international experts in head and neck cancer surgical, radiation, and medical oncology, representing 35 international professional societies and national clinical trial groups. Endorsed by 39 societies and professional bodies, these consensus practice recommendations aim to decrease inconsistency of practice, reduce uncertainty in care, and provide reassurance for clinicians worldwide for head and neck surgical oncology in the context of the COVID-19 pandemic and in the setting of acute severe resource constraint and high risk of infection to patients and staff.
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http://dx.doi.org/10.1016/S1470-2045(20)30334-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289563PMC
July 2020

GATA2 Regulates Constitutive PD-L1 and PD-L2 Expression in Brain Tumors.

Sci Rep 2020 06 3;10(1):9027. Epub 2020 Jun 3.

Department of Neurological Surgery, Washington University School of Medicine, St. Louis, Missouri, USA.

Encouraging clinical results using immune checkpoint therapies to target the PD-1 axis in a variety of cancer types have paved the way for new immune therapy trials in brain tumor patients. However, the molecular mechanisms that regulate expression of the PD-1 pathway ligands, PD-L1 and PD-L2, remain poorly understood. To address this, we explored the cell-intrinsic mechanisms of constitutive PD-L1 and PD-L2 expression in brain tumors. PD-L1 and PD-L2 expression was assessed by flow cytometry and qRT-PCR in brain tumor cell lines and patient tumor-derived brain tumor-initiating cells (BTICs). Immunologic effects of PD-L2 overexpression were evaluated by IFN-γ ELISPOT. CD274 and PDCD1LG2 cis-regulatory regions were cloned from genomic DNA and assessed in full or by mutating and/or deleting regulatory elements by luciferase assays. Correlations between clinical responses and PD-L1 and PD-L2 expression status were evaluated in TCGA datasets in LGG and GBM patients. We found that a subset of brain tumor cell lines and BTICs expressed high constitutive levels of PD-L1 and PD-L2 and that PD-L2 overexpression inhibited neoantigen specific T cell IFN-γ production. Characterization of novel cis-regulatory regions in CD274 and PDCD1LG2 lead us to identify that GATA2 is sufficient to drive PD-L1 and PD-L2 expression and is necessary for PD-L2 expression. Importantly, in TCGA datasets, PD-L2 correlated with worse clinical outcomes in glioma patients.. By perturbing GATA2 biology, targeted therapies may be useful to decrease inhibitory effects of PD-L2 in the microenvironment.
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http://dx.doi.org/10.1038/s41598-020-65915-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7271235PMC
June 2020

Perioperative nasal and paranasal sinus considerations in transsphenoidal surgery for pituitary disease.

Br J Neurosurg 2020 Jun 25;34(3):246-252. Epub 2020 Feb 25.

Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Endoscopic endonasal skull base surgery has emerged as the treatment modality of choice for a range of skull base lesions, particularly pituitary adenomas. However, navigation and manipulation of the nasal corridor and paranasal sinuses requires that surgeons are aware of effective techniques to maximize patient outcomes and avoid sinonasal morbidity postoperatively. This paper is a narrative review aimed to provide an updated and consolidated report on the perioperative management of the nasal corridor and paranasal sinuses in the setting of endoscopic skull base surgery for pituitary disease. Anatomic variants and common surgical techniques are discussed. Post-operative complications are evaluated in detail. Understanding the structural implications of the endonasal approach to the sphenoid is crucial to optimization of the surgical outcomes. We propose guidelines for perioperative management of endoscopic endonasal skull base surgery for pituitary diseases. Standardized treatment algorithms can improve patient satisfaction, and increase the comparability and the quality of reported information across research studies.
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http://dx.doi.org/10.1080/02688697.2020.1731424DOI Listing
June 2020

Galectin-1-driven T cell exclusion in the tumor endothelium promotes immunotherapy resistance.

J Clin Invest 2019 12;129(12):5553-5567

Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California, USA.

Immune checkpoint inhibitors (ICIs), although promising, have variable benefit in head and neck cancer (HNC). We noted that tumor galectin-1 (Gal1) levels were inversely correlated with treatment response and survival in patients with HNC who were treated with ICIs. Using multiple HNC mouse models, we show that tumor-secreted Gal1 mediates immune evasion by preventing T cell migration into the tumor. Mechanistically, Gal1 reprograms the tumor endothelium to upregulate cell-surface programmed death ligand 1 (PD-L1) and galectin-9. Using genetic and pharmacological approaches, we show that Gal1 blockade increases intratumoral T cell infiltration, leading to a better response to anti-PD1 therapy with or without radiotherapy. Our study reveals the function of Gal1 in transforming the tumor endothelium into an immune-suppressive barrier and that its inhibition synergizes with ICIs.
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http://dx.doi.org/10.1172/JCI129025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6877340PMC
December 2019

Neoadjuvant PD-1 Immune Checkpoint Blockade Reverses Functional Immunodominance among Tumor Antigen-Specific T Cells.

Clin Cancer Res 2020 02 23;26(3):679-689. Epub 2019 Oct 23.

Translational Tumor Immunology Program, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland.

Purpose: Surgical resection of primary tumor with regional lymphadenectomy remains the treatment of choice for patients with advanced human papillomavirus-negative head and neck squamous cell carcinoma. However, even when pathologic disease-free margins can be achieved, locoregional and/or distant disease relapse remains high. Perioperative immunotherapy may improve outcomes, but mechanistic data supporting the use of neoadjuvant or adjuvant treatment clinically are sparse.

Experimental Design: Two syngeneic models of oral cavity carcinoma with defined T-cell antigens were treated with programmed death receptor 1 (PD-1) mAb before or after surgical resection of primary tumors, and antigen-specific T-cell responses were explored with functional and challenge assays.

Results: We demonstrated that functional immunodominance developed among T cells targeting multiple independent tumor antigens. T cells specific for subdominant antigens expressed greater levels of PD-1. Neoadjuvant, but not adjuvant, PD-1 immune checkpoint blockade broke immunodominance and induced T-cell responses to dominant and subdominant antigens. Using tumors lacking the immunodominant antigen as a model of antigen escape, neoadjuvant PD-1 immune checkpoint blockade induced effector T-cell immunity against tumor cells lacking immunodominant but retaining subdominant antigen. When combined with complete surgical excision, neoadjuvant PD-1 immune checkpoint blockade led to formation of immunologic memory capable of preventing engraftment of tumors lacking the immunodominant but retaining subdominant antigen.

Conclusions: Together, these results implicate PD-1 expression by T cells in the mechanism of functional immunodominance among independent T-cell clones within a progressing tumor and support the use of neoadjuvant PD-1 immune checkpoint blockade in patients with surgically resectable carcinomas.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-2209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002203PMC
February 2020

Open-Sourced CIViC Annotation Pipeline to Identify and Annotate Clinically Relevant Variants Using Single-Molecule Molecular Inversion Probes.

JCO Clin Cancer Inform 2019 10;3:1-12

Washington University School of Medicine, St Louis, MO.

Purpose: Clinical targeted sequencing panels are important for identifying actionable variants for patients with cancer; however, existing approaches do not provide transparent and rationally designed clinical panels to accommodate the rapidly growing knowledge within oncology.

Materials And Methods: We used the Clinical Interpretations of Variants in Cancer (CIViC) database to develop an Open-Sourced CIViC Annotation Pipeline (OpenCAP). OpenCAP provides methods to identify variants within the CIViC database, build probes for variant capture, use probes on prospective samples, and link somatic variants to CIViC clinical relevance statements. OpenCAP was tested using a single-molecule molecular inversion probe (smMIP) capture design on 27 cancer samples from 5 tumor types. In total, 2,027 smMIPs were designed to target 111 eligible CIViC variants (61.5 kb of genomic space).

Results: When compared with orthogonal sequencing, CIViC smMIP sequencing demonstrated a 95% sensitivity for variant detection (n = 61 of 64 variants). Variant allele frequencies for variants identified on both sequencing platforms were highly concordant (Pearson's = 0.885; n = 61 variants). Moreover, for individuals with paired tumor and normal samples (n = 12), 182 clinically relevant variants missed by orthogonal sequencing were discovered by CIViC smMIP sequencing.

Conclusion: The OpenCAP design paradigm demonstrates the utility of an open-source and open-access database built on attendant community contributions with peer-reviewed interpretations. Use of a public repository for variant identification, probe development, and variant interpretation provides a transparent approach to build dynamic next-generation sequencing-based oncology panels.
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http://dx.doi.org/10.1200/CCI.19.00077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6873961PMC
October 2019

Targeting EZH2 Enhances Antigen Presentation, Antitumor Immunity, and Circumvents Anti-PD-1 Resistance in Head and Neck Cancer.

Clin Cancer Res 2020 01 27;26(1):290-300. Epub 2019 Sep 27.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Purpose: Anti-programmed death-1 (PD-1) receptor-based therapeutics improve survival in patients with recurrent head and neck squamous cell carcinoma (HNSCC), but many do not benefit due to a low response rate. Herein, we identified EZH2 as a therapeutic target that enhanced tumor cell antigen presentation and subsequently sensitized resistant tumors to anti-PD-1 therapy.

Experimental Design: EZH2 regulation of antigen presentation was defined using EZH2 inhibitors (GSK126 and EPZ6438) in human and mouse HNSCC cell lines. Mechanistic dissection of EZH2 in regulation of antigen presentation was investigated using flow cytometry, qRT-PCR, ELISA, and chromatin-immunoprecipitation assays. -deficient cell lines were generated using CRISPR-CAS9. GSK126 and anti-PD-1-blocking antibody were used in testing combinatorial therapy .

Results: EZH2 expression was negatively correlated with antigen-processing machinery pathway components in HNSCC data sets in The Cancer Genome Atlas. EZH2 inhibition resulted in significant upregulation of MHC class I expression in human and mouse human papillomavirus-negative HNSCC lines and in mouse models . Enhanced antigen presentation on the tumor cells by EZH2 inhibitors or CRISPR-mediated EZH2 deficiency increased antigen-specific CD8 T-cell proliferation, IFNγ production, and tumor cell cytotoxicity. Mechanistically, EZH2 inhibition reduced the histone H3K27me3 modification on the β-2-microglobulin promoter. Finally, in an anti-PD-1-resistant model of HNSCC, tumor growth was suppressed with combination therapy.

Conclusions: Our results demonstrated that targeting EZH2 enhanced antigen presentation and was able to circumvent anti-PD-1 resistance. Thus, combining EZH2 targeting with anti-PD-1 may increase therapeutic susceptibility in HNSCC.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6942613PMC
January 2020

Disparities in Oral Cancer Screening Among Dental Professionals: NHANES 2011-2016.

Am J Prev Med 2019 10 20;57(4):447-457. Epub 2019 Aug 20.

Division of Oral Medicine, Brigham and Women's Hospital and Dana-Farber Cancer Institute, Boston, Massachusetts; Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts.

Introduction: As early detection of oral cancers is associated with better survival, oral cancer screening should be included in dental visits for adults. This study examines the rate and predictors of oral cancer screening exams among U.S. adults with a recent dental visit.

Methods: Individuals aged ≥30 years who received a dental visit in the last 2 years, in the 2011-2016 National Health and Nutrition Examination Survey were analyzed in December 2018. Weighted multivariable logistic regression models examined the likelihood of intraoral and extraoral oral cancer screening exams, adjusting for age, sex, race/ethnicity, education, marital status, poverty income ratio, health insurance, tobacco smoking, and alcohol consumption. Subgroup analyses were conducted among races/ethnicities, smokers, and alcohol consumers. Statistical significance was set at p<0.01.

Results: A total of 37.6% and 31.3% reported receiving an intraoral and extraoral oral cancer screening exam, respectively. Minority racial/ethnic groups versus white, non-Hispanics, less-educated versus more-educated, uninsured and Medicaid-insured versus privately insured, and low-income versus high-income participants were less likely to have received intraoral or extraoral oral cancer screening exams. There was no difference in the likelihood of being screened based on smoking status. Alcohol consumers were more likely to be screened. Among subgroups, less-educated and low-income individuals were less likely to be screened.

Conclusions: A significantly higher proportion of minority race/ethnicity and low SES individuals report not receiving an oral cancer screening exam, despite a recent dental visit. This selective screening by dental professionals is incompliant with guidelines and concerning because these groups are more likely to present with an advanced stage of oral cancer at diagnosis. An understanding of the reasons for discriminatory oral cancer screening practices could help develop effective interventions.
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http://dx.doi.org/10.1016/j.amepre.2019.04.026DOI Listing
October 2019

The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of squamous cell carcinoma of the head and neck (HNSCC).

J Immunother Cancer 2019 07 15;7(1):184. Epub 2019 Jul 15.

UPMC Hillman Cancer Center, Pittsburgh, PA, USA.

Head and neck cancers, including those of the lip and oral cavity, nasal cavity, paranasal sinuses, oropharynx, larynx and nasopharynx represent nearly 700,000 new cases and 380,000 deaths worldwide per annum, and account for over 10,000 annual deaths in the United States alone. Improvement in outcomes are needed for patients with recurrent and or metastatic squamous cell carcinoma of the head and neck (HNSCC). In 2016, the US Food and Drug Administration (FDA) granted the first immunotherapeutic approvals - the anti-PD-1 immune checkpoint inhibitors nivolumab and pembrolizumab - for the treatment of patients with recurrent squamous cell carcinoma of the head and neck (HNSCC) that is refractory to platinum-based regimens. The European Commission followed in 2017 with approval of nivolumab for treatment of the same patient population, and shortly thereafter with approval of pembrolizumab monotherapy for the treatment of recurrent or metastatic HNSCC in adults whose tumors express PD-L1 with a ≥ 50% tumor proportion score and have progressed on or after platinum-containing chemotherapy. Then in 2019, the FDA granted approval for PD-1 inhibition as first-line treatment for patients with metastatic or unresectable, recurrent HNSCC, approving pembrolizumab in combination with platinum and fluorouracil for all patients with HNSCC and pembrolizumab as a single agent for patients with HNSCC whose tumors express a PD-L1 combined positive score ≥ 1. These approvals marked the first new therapies for these patients since 2006, as well as the first immunotherapeutic approvals in this disease. In light of the introduction of these novel therapies for the treatment of patients with head and neck cancer, The Society for Immunotherapy of Cancer (SITC) formed an expert committee tasked with generating consensus recommendations for emerging immunotherapies, including appropriate patient selection, therapy sequence, response monitoring, adverse event management, and biomarker testing. These consensus guidelines serve as a foundation to assist clinicians' understanding of the role of immunotherapies in this disease setting, and to standardize utilization across the field for patient benefit. Due to country-specific variances in approvals, availability and regulations regarding the discussed agents, this panel focused solely on FDA-approved drugs for the treatment of patients in the U.S.
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http://dx.doi.org/10.1186/s40425-019-0662-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6632213PMC
July 2019

Accounting for proximal variants improves neoantigen prediction.

Nat Genet 2019 01 3;51(1):175-179. Epub 2018 Dec 3.

McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA.

Recent efforts to design personalized cancer immunotherapies use predicted neoantigens, but most neoantigen prediction strategies do not consider proximal (nearby) variants that alter the peptide sequence and may influence neoantigen binding. We evaluated somatic variants from 430 tumors to understand how proximal somatic and germline alterations change the neoantigenic peptide sequence and also affect neoantigen binding predictions. On average, 241 missense somatic variants were analyzed per sample. Of these somatic variants, 5% had one or more in-phase missense proximal variants. Without incorporating proximal variant correction for major histocompatibility complex class I neoantigen peptides, the overall false discovery rate (incorrect neoantigens predicted) and the false negative rate (strong-binding neoantigens missed) across peptides of lengths 8-11 were estimated as 0.069 (6.9%) and 0.026 (2.6%), respectively.
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http://dx.doi.org/10.1038/s41588-018-0283-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6309579PMC
January 2019

A deep learning approach to automate refinement of somatic variant calling from cancer sequencing data.

Nat Genet 2018 12 5;50(12):1735-1743. Epub 2018 Nov 5.

McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA.

Cancer genomic analysis requires accurate identification of somatic variants in sequencing data. Manual review to refine somatic variant calls is required as a final step after automated processing. However, manual variant refinement is time-consuming, costly, poorly standardized, and non-reproducible. Here, we systematized and standardized somatic variant refinement using a machine learning approach. The final model incorporates 41,000 variants from 440 sequencing cases. This model accurately recapitulated manual refinement labels for three independent testing sets (13,579 variants) and accurately predicted somatic variants confirmed by orthogonal validation sequencing data (212,158 variants). The model improves on manual somatic refinement by reducing bias on calls otherwise subject to high inter-reviewer variability.
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http://dx.doi.org/10.1038/s41588-018-0257-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6428590PMC
December 2018

Radiologic predictors of immune checkpoint inhibitor response in advanced head and neck squamous cell carcinoma.

Oral Oncol 2018 10 17;85:29-34. Epub 2018 Aug 17.

Department of Radiation Oncology, Brigham and Women's Hospital and Dana-Farber Cancer Institute, Boston, MA 703-389-1895, United States. Electronic address:

Radiologic predictors of response to immune checkpoint blockade (ICPi) in advanced head and neck squamous cell carcinoma (HNSCC) patients could help guide patient selection and management. We analyzed a large institutional cohort of 100 consecutive HNSCC patients treated with ICPi to investigate associations between molecular and radiologic phenotype and assess radiologic predictors of response and survival. Of particular interest was the impact of increased total tumor burden (TB), calculated as the sum of the largest diameter of all measurable lesions according to RECIST 1.1, and early radiologic indicators of response versus progression. Within our cohort, 42% of patients had HPV+ associated disease, 64% had persistent/recurrent head and neck lesions, and 77% had distant metastases. Median TB was 5.4 cm. HPV+ disease and increased total mutational burden were associated with distant disease in the absence of locoregional disease (p < 0.01 and p = 0.03, respectively). Forty patients (40%) demonstrated clinical benefit to ICPi, and the median overall survival (OS) on PD-1 therapy was 4.5 months. A lower tumor burden at baseline was associated with clinical benefit (p = 0.03) and improved OS (p < 0.01, HR 2.33). There was only one instance of pseudoprogression; indeed any increase in TB on first interval scan was associated with poor OS (p = 0.02, HR 2.39). These data suggest that HNSCC patients who benefit from ICPi are more likely to have lower tumor burden at the onset of treatment and minimal increase in tumor burden while on treatment.
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http://dx.doi.org/10.1016/j.oraloncology.2018.08.005DOI Listing
October 2018

Improved outcomes in PI3K-pathway-altered metastatic HPV oropharyngeal cancer.

JCI Insight 2018 09 6;3(17). Epub 2018 Sep 6.

Department of Pathology and.

While it has been recognized that human papillomavirus-associated (HPV-associated) oropharyngeal cancer (OPC) portends an improved prognosis, distinct patterns of disease recurrence have emerged. Molecular characterization of this subset of HPV patients remains unexplored. We evaluated 52 metastatic HPV+ OPC patients from our institution and paired massively parallel sequencing data with clinical parameters and survival outcomes in 81% of patients. Genomic data were then compared with 2 molecularly defined, curable HPV+ cohorts. Metastatic HPV+ OPC patients with pulmonary-only metastases demonstrated worse outcomes. Nonexclusive somatic alterations in KMT2D and PIK3CA were most frequent, with PRKDC alterations occurring at higher frequency when compared with all sequenced HPV+ OPC patients. PI3K pathway alterations were associated with improved outcomes among metastatic HPV+ OPC patients. We demonstrate subtle differences in the mutational landscape between curable and metastatic HPV+ OPC populations, with a trend towards more frequent DNA repair protein alterations in the latter. We demonstrate improved outcomes when PI3K pathway alterations are present in these patients. We provide molecular insights for this important HPV+ subgroup that have significant therapeutic implications.
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http://dx.doi.org/10.1172/jci.insight.122799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6171803PMC
September 2018

Oral Cavity Squamous Cell Carcinoma Xenografts Retain Complex Genotypes and Intertumor Molecular Heterogeneity.

Cell Rep 2018 08;24(8):2167-2178

McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO 63108, USA; Department of Medicine, Division of Medical Oncology, Washington University School of Medicine, St. Louis, MO 63108, USA; Department of Genetics, Washington University School of Medicine, St. Louis, MO 63108, USA; Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63108, USA. Electronic address:

Herein, we report an oral cavity squamous cell carcinoma (OCSCC) patient-derived xenograft (PDX) platform, with genomic annotation useful for co-clinical trial and mechanistic studies. Genomic analysis included whole-exome sequencing (WES) and transcriptome sequencing (RNA-seq) on 16 tumors and matched PDXs and additional whole-genome sequencing (WGS) on 9 of these pairs as a representative subset of a larger OCSCC PDX repository (n = 63). In 12 models with high purity, more than 90% of variants detected in the tumor were retained in the matched PDX. The genomic landscape across these PDXs reflected OCSCC molecular heterogeneity, including previously described basal, mesenchymal, and classical molecular subtypes. To demonstrate the integration of PDXs into a clinical trial framework, we show that pharmacological intervention in PDXs parallels clinical response and extends patient data. Together, these data describe a repository of OCSCC-specific PDXs and illustrate conservation of primary tumor genotypes, intratumoral heterogeneity, and co-clinical trial application.
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http://dx.doi.org/10.1016/j.celrep.2018.07.058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6417872PMC
August 2018

Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses.

Nat Med 2018 08 23;24(8):1143-1150. Epub 2018 Jul 23.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Mesenchymal tumor subpopulations secrete pro-tumorigenic cytokines and promote treatment resistance. This phenomenon has been implicated in chemorefractory small cell lung cancer and resistance to targeted therapies, but remains incompletely defined. Here, we identify a subclass of endogenous retroviruses (ERVs) that engages innate immune signaling in these cells. Stimulated 3 prime antisense retroviral coding sequences (SPARCS) are oriented inversely in 3' untranslated regions of specific genes enriched for regulation by STAT1 and EZH2. Derepression of these loci results in double-stranded RNA generation following IFN-γ exposure due to bi-directional transcription from the STAT1-activated gene promoter and the 5' long terminal repeat of the antisense ERV. Engagement of MAVS and STING activates downstream TBK1, IRF3, and STAT1 signaling, sustaining a positive feedback loop. SPARCS induction in human tumors is tightly associated with major histocompatibility complex class 1 expression, mesenchymal markers, and downregulation of chromatin modifying enzymes, including EZH2. Analysis of cell lines with high inducible SPARCS expression reveals strong association with an AXL/MET-positive mesenchymal cell state. While SPARCS-high tumors are immune infiltrated, they also exhibit multiple features of an immune-suppressed microenviroment. Together, these data unveil a subclass of ERVs whose derepression triggers pathologic innate immune signaling in cancer, with important implications for cancer immunotherapy.
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http://dx.doi.org/10.1038/s41591-018-0116-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6082722PMC
August 2018

Evaluating the PD-1 Axis and Immune Effector Cell Infiltration in Oropharyngeal Squamous Cell Carcinoma.

Int J Radiat Oncol Biol Phys 2018 09 29;102(1):137-145. Epub 2018 Jun 29.

Department of Radiation Oncology, Brigham & Women's Hospital/Dana-Farber Cancer Institute, Boston, Massachusetts.

Purpose: Programmed death-1 (PD-1) inhibitors are approved for the treatment of patients with recurrent and metastatic squamous cell carcinoma of the head and neck (SCCHN). Ongoing and planned randomized phase 3 trials are testing the benefit of combining PD-1/programmed death-ligand 1 (PD-L1) inhibitors with chemoradiation for patients with locoregionally confined SCCHN. Few studies have investigated relationships among potential predictive pathologic biomarkers such as PD-L1, PD-L2, and PD-1 in this population and associations between these markers and clinical characteristics.

Methods And Materials: We retrospectively reviewed records and pathology from 81 patients with locoregional oropharynx SCCHN treated with curative intent. Samples were analyzed for PD-L1, PD-L2, PD-1, CD8, and CD56 expression using immunohistochemistry. Human papilloma virus (HPV) status was determined by p16-immunohistochemistry and confirmed by in situ hybridization or polymerase chain reaction-based HPV typing. Correlations between HPV status, clinical features, and recurrence status with immune markers in both tumor and tumor-associated stroma were determined. Hazard ratios were estimated via Cox proportional hazards model.

Results: Tumor PD-L1 expression was inversely associated with age (P = .01) and the highest levels of expression (>30% of tumor cells) were observed in HPV-associated tumors. There was a correlation between tumor and stromal PD-L1 expression (P = < .0001). PD-1 and CD8 expression within tumor deposits was associated with HPV status (P = 0.003 and P = .008, respectively) and decreased local recurrence (P = .001 and P < .001, respectively). In addition to the association between tumor and stromal PD-1 (P < .0001), PD-1 was also correlated with tumor PD-L1 expression (P < .001). CD56+ natural killer cell infiltrates correlated with PD-L1 expression.

Conclusions: In patients with untreated oropharyngeal SCCHN, HPV-associated tumors displayed the highest levels of PD-L1 expression and PD-1+ and CD8+ immune cells. Locally recurrent tumors had lower levels of PD-L1, PD-1, and CD-8 positivity. Whereas almost all SCCHN tumors had CD56+ infiltrating natural killer cells, most tumors didn't have PD-L2 expression. These associations may help predict which patients may benefit most from immunotherapeutic approaches.
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http://dx.doi.org/10.1016/j.ijrobp.2018.05.002DOI Listing
September 2018

Integrated genomic characterization of oral carcinomas in post-hematopoietic stem cell transplantation survivors.

Oral Oncol 2018 06 10;81:1-9. Epub 2018 Apr 10.

Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, USA.

Objectives: Secondary oral squamous cell carcinoma (OSCC) is a late complication in allogeneic hematopoietic stem cell transplantation (HSCT) patients, but little is known about long-term outcomes and prognostication. Additionally, molecular alterations and immunologic insights unique to this disease remain largely unexplored.

Methods: We present a cohort of 31 patients with post-HSCT OSCC and reported on clinicopathologic predictors of survival. Whole-exome sequencing was performed on 6 (19%) matched pairs of peripheral blood (post-conditioning, pre-HSCT) and tumor samples. The entire cohort had archival tumor available for immunoprofiling with PD-1/L1 immunohistochemistry.

Results: Five-year overall survival (OS) was 57% (95% CI: 46.1-69.8) with a median disease-free survival (DFS) of 13.3 months. Advanced initial staging, a buccal or oral tongue subsite, chronic oral graft-versus-host disease (GVHD) and smoking all negatively impacted survival. High tumor mutational burden (TMB) (median 11.3 vs. 5.0) and unique mutational signatures were noted between unrelated and related donor groups - with a strong correlation between infiltrating PD-1+ lymphocytes and TMB (R = 0.98, p < 0.01). Some differences were observed when comparing commonly mutated genes among our cohort and TCGA, with a predominance of TP53 events.

Conclusion: Survival outcomes appear similar in HSCT survivors with OSCC compared with non-HSCT OSCC populations. We identified somatic alterations in genes with therapeutic potential unique to this subpopulation of oral cancers.
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http://dx.doi.org/10.1016/j.oraloncology.2018.04.007DOI Listing
June 2018

Frameshift events predict anti-PD-1/L1 response in head and neck cancer.

JCI Insight 2018 02 22;3(4). Epub 2018 Feb 22.

Department of Medical Oncology, and.

Programmed cell death protein 1 (PD-1) inhibitors have efficacy in treating squamous cell carcinoma of the head and neck (SCCHN), but objective response rates are low. PD-1 ligand (PD-L1) expression alone is not considered a robust predictor of response and additional biomarkers are needed. This 3-year observational cohort followed 126 SCCHN patients treated with anti-PD-1/L1 therapy. Prior to treatment, 81 (64%) had targeted massively parallel tumor sequencing. Of these, 42 (52%) underwent fluorescence-activated cell sorting and PD-L1 immunohistochemistry for tumor immunoprofiling. Six (5%) complete responses (CRs) and 11 (9%) partial responses (PRs) were observed. Those treated with prior chemotherapy (98, 78%) versus only surgery and/or radiation had longer overall survival (OS) (10 vs. 3 months, P = 0.02). Smokers had a higher total mutational burden (TMB) (P = 0.01). Virus-positive patients had a lower TMB (P < 0.01) and improved OS (P = 0.02). Among virus-negative responders, NOTCH1 and SMARCA4 were more frequently mutated and frameshift events in tumor suppressor genes occurred more frequently (P = 0.03). Higher TMB and CD8+ T cell infiltrates predicted anti-PD-1/L1 benefit (P < 0.01, P < 0.01, respectively) among virus-negative tumors. TIM-3/LAG-3 coexpression with PD-1 was higher on T cells among nonresponders (P = 0.03 and 0.02, respectively). Somatic frameshift events in tumor suppressor genes and higher TMB among virus-negative SCCHN tumors predict anti-PD-1/L1 response.
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http://dx.doi.org/10.1172/jci.insight.98811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5916245PMC
February 2018

Cancer immunogenomic approach to neoantigen discovery in a checkpoint blockade responsive murine model of oral cavity squamous cell carcinoma.

Oncotarget 2018 Jan 28;9(3):4109-4119. Epub 2017 Dec 28.

Dana-Farber Cancer Institute, Boston, MA, USA.

Head and neck squamous cell carcinomas (HNSCC) are an ideal immunotherapy target due to their high mutation burden and frequent infiltration with lymphocytes. Preclinical models to investigate targeted and combination therapies as well as defining biomarkers to guide treatment represent an important need in the field. Immunogenomics approaches have illuminated the role of mutation-derived tumor neoantigens as potential biomarkers of response to checkpoint blockade as well as representing therapeutic vaccines. Here, we aimed to define a platform for checkpoint and other immunotherapy studies using syngeneic HNSCC cell line models (MOC2 and MOC22), and evaluated the association between mutation burden, predicted neoantigen landscape, infiltrating T cell populations and responsiveness of tumors to anti-PD1 therapy. We defined dramatic hematopoietic cell transcriptomic alterations in the MOC22 anti-PD1 responsive model in both tumor and draining lymph nodes. Using a cancer immunogenomics pipeline and validation with ELISPOT and tetramer analysis, we identified the H-2Kb-restricted ICAM1 (mICAM1) as a neoantigen in MOC22. Finally, we demonstrated that mICAM1 vaccination was able to protect against MOC22 tumor development defining mICAM1 as a bona fide neoantigen. Together these data define a pre-clinical HNSCC model system that provides a foundation for future investigations into combination and novel therapeutics.
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http://dx.doi.org/10.18632/oncotarget.23751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5790525PMC
January 2018

Anti-Trop2 blockade enhances the therapeutic efficacy of ErbB3 inhibition in head and neck squamous cell carcinoma.

Cell Death Dis 2018 01 5;9(1). Epub 2018 Jan 5.

Memorial Sloan-Kettering Cancer Center, Monmouth, NJ, USA.

ErbB3 has been widely implicated in treatment resistance, but its role as a primary treatment target is less clear. Canonically ErbB3 requires EGFR or ErbB2 for activation, whereas these two established treatment targets are thought to signal independently of ErbB3. In this study, we show that ErbB3 is essential for tumor growth of treatment-naive HNSCC patient-derived xenografts. This ErbB3 dependency occurs via ErbB3-mediated control of EGFR activation and HIF1α stabilization, which require ErbB3 and its ligand neuregulin-1. Here, we show that ErbB3 antibody treatment selects for a population of ErbB3-persister cells that express high levels of the transmembrane protein Trop2 that we previously identified as an inhibitor of ErbB3. Co-treatment with anti-ErbB3 and anti-Trop2 antibodies is synergistic and produces a greater anti-tumor response than either antibody alone. Collectively, these data both compel a revision of ErbB-family signaling and delineate a strategy for its effective inhibition in HNSCC.
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http://dx.doi.org/10.1038/s41419-017-0029-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5849045PMC
January 2018

CD271 Confers an Invasive and Metastatic Phenotype of Head and Neck Squamous Cell Carcinoma through the Upregulation of Slug.

Clin Cancer Res 2018 02 5;24(3):674-683. Epub 2017 Dec 5.

Division of Head and Neck Surgery, Department of Otolaryngology, Stanford Cancer Institute, Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California.

Head and neck squamous cell carcinoma (HNSCC) is comprised of heterogeneous populations of cells, and CD271 (NGFR; p75NTR) has been associated with a tumor-initiating cell subpopulation. This study assessed the role of CD271 in modulating metastatic behavior in HNSCC. CD271 was overexpressed in murine and human oral squamous cell carcinoma cells to assess the impact of CD271 activation on the invasive and metastatic phenotype of these cells, using and orthotopic modeling. Treatment with human nerve growth factor (NGF) to activate CD271, as well as shRNA knockdown of the CD271-upregulated expression, was used to assess the mechanism of the CD271-induced invasive phenotype. Relevance of CD271 expression in human HNSCC was evaluated in patient-derived xenografts (PDX) and primary human oral cancers, annotated with clinical behavior characteristics and survival data. Forced expression of CD271 resulted in a more invasive and metastatic phenotype. Slug, an epithelial-to-mesenchymal transition (EMT)-related transcription factor, encoded by , was highly expressed in MOC2-CD271 and HSC3-CD271, compared with respective parental cells. CD271 activation by NGF conferred enhanced invasiveness in CD271-overexpressing cells, which was abrogated by knockdown. In PDXs and primary human HNSCC, CD271 expression correlated with higher expression, greater nodal metastasis, and shorter disease-free survival. Activation of CD271 results in upregulation of /Slug, which, in turn, results in a more invasive phenotype and an enhanced capacity for metastasis to regional lymph nodes. These findings point to CD271 as a promising, therapeutic target for oral cancer metastasis. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-0866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6713647PMC
February 2018