Publications by authors named "Jose R Conejo-Garcia"

107 Publications

Wide and deep learning for automatic cell type identification.

Comput Struct Biotechnol J 2021 26;19:1052-1062. Epub 2021 Jan 26.

Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, 12902 USF Magnolia Drive, Tampa, FL 33612, USA.

Cell type classification is an important problem in cancer research, especially with the advent of single cell technologies. Correctly identifying cells within the tumor microenvironment can provide oncologists with a snapshot of how a patient's immune system reacts to the tumor. Wide and deep learning (WDL) is an approach to construct a cell-classification prediction model that can learn patterns within high-dimensional data (deep) and ensure that biologically relevant features (wide) remain in the final model. In this paper, we demonstrate that regularization can prevent overfitting and adding a wide component to a neural network can result in a model with better predictive performance. In particular, we observed that a combination of dropout and regularization can lead to a validation loss function that does not depend on the number of training iterations and does not experience a significant decrease in prediction accuracy compared to models with , dropout, or no regularization. Additionally, we show WDL can have superior classification accuracy when the training and testing of a model are completed data on that arise from the same cancer type but different platforms. More specifically, WDL compared to traditional deep learning models can substantially increase the overall cell type prediction accuracy (36.5 to 86.9%) and T cell subtypes (CD4: 2.4 to 59.1%, and CD8: 19.5 to 96.1%) when the models were trained using melanoma data obtained from the 10X platform and tested on basal cell carcinoma data obtained using SMART-seq. WDL obtains higher accuracy when compared to state-of-the-art cell classification algorithms CHETAH (70.36%) and SingleR (70.59%).
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http://dx.doi.org/10.1016/j.csbj.2021.01.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878986PMC
January 2021

Circulating Biomarkers of Inflammation and Ovarian Cancer Risk in the Nurses' Health Studies.

Cancer Epidemiol Biomarkers Prev 2021 Feb 9. Epub 2021 Feb 9.

Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.

Background: Chronic inflammation is a well-established mechanism of ovarian carcinogenesis; however, the specific immunogenic processes influencing ovarian tumor development remain unclear. In a case-control study nested within the Nurses' Health Study (NHS) and the NHSII, we examined the association between six inflammatory chemokines and cytokines [B-cell activating factor (BAFF), C-X-C motif chemokine ligand 13 (CXCL13), IL8, soluble(s)IL2-receptor-α(Rα), sIL6Rα] and epithelial ovarian cancer risk.

Methods: Among 299 epithelial ovarian cancer cases and 334 matched controls, six inflammatory biomarkers were measured in plasma collected 1-24 years before diagnosis or index date using two custom multiplex Luminex panels. ORs and 95% confidence intervals (CI) were estimated for the association between each biomarker and risk using multivariable conditional logistic regression with adjustment for relevant confounders. We additionally assessed heterogeneity in the risk associations by histotype [high-grade serous carcinoma (HGSC) vs. non-HGSC], body mass index, smoking status, menopausal status, and aspirin use.

Results: Women with the highest versus lowest quartile (Q) levels of CXCL13 had a 72% increased ovarian cancer risk (OR = 1.72; 95% CI = 1.04-2.83; = 0.007). The positive association with CXCL13 was stronger in magnitude for non-HGSC, overweight or obese women, and postmenopausal women, although only menopausal status demonstrated statistically significant heterogeneity ( = 0.04). The remaining biomarkers were not associated with risk.

Conclusions: This first evidence that prediagnostic CXCL13, a B-cell chemoattractant, is associated with an increased risk of epithelial ovarian cancer expands current understanding of the role of inflammation in ovarian carcinogenesis.

Impact: CXCL13 may represent a novel biomarker for ovarian cancer.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1390DOI Listing
February 2021

IgA transcytosis and antigen recognition govern ovarian cancer immunity.

Nature 2021 Feb 3. Epub 2021 Feb 3.

Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.

Most ovarian cancers are infiltrated by prognostically relevant activated T cells, yet exhibit low response rates to immune checkpoint inhibitors. Memory B cell and plasma cell infiltrates have previously been associated with better outcomes in ovarian cancer, but the nature and functional relevance of these responses are controversial. Here, using 3 independent cohorts that in total comprise 534 patients with high-grade serous ovarian cancer, we show that robust, protective humoral responses are dominated by the production of polyclonal IgA, which binds to polymeric IgA receptors that are universally expressed on ovarian cancer cells. Notably, tumour B-cell-derived IgA redirects myeloid cells against extracellular oncogenic drivers, which causes tumour cell death. In addition, IgA transcytosis through malignant epithelial cells elicits transcriptional changes that antagonize the RAS pathway and sensitize tumour cells to cytolytic killing by T cells, which also contributes to hindering malignant progression. Thus, tumour-antigen-specific and -antigen-independent IgA responses antagonize the growth of ovarian cancer by governing coordinated tumour cell, T cell and B cell responses. These findings provide a platform for identifying targets that are spontaneously recognized by intratumoural B-cell-derived antibodies, and suggest that immunotherapies that augment B cell responses may be more effective than approaches that focus on T cells, particularly for malignancies that are resistant to checkpoint inhibitors.
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http://dx.doi.org/10.1038/s41586-020-03144-0DOI Listing
February 2021

Th1 cytokine interferon gamma improves response in HER2 breast cancer by modulating the ubiquitin proteasomal pathway.

Mol Ther 2021 Jan 5. Epub 2021 Jan 5.

Clinical Science & Immunology Program, H. Lee Moffitt Cancer Center, Tampa, FL, USA; Department of Breast Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA. Electronic address:

HER2 breast cancer (BC) remains a significant problem in patients with locally advanced or metastatic BC. We investigated the relationship between T helper 1 (Th1) immune response and the proteasomal degradation pathway (PDP), in HER2-sensitive and -resistant cells. HER2 overexpression is partially maintained because E3 ubiquitin ligase Cullin5 (CUL5), which degrades HER2, is frequently mutated or underexpressed, while the client-protective co-chaperones cell division cycle 37 (Cdc37) and heat shock protein 90 (Hsp90) are increased translating to diminished survival. The Th1 cytokine interferon (IFN)-γ caused increased CUL5 expression and marked dissociation of both Cdc37 and Hsp90 from HER2, causing significant surface loss of HER2, diminished growth, and induction of tumor senescence. In HER2-resistant mammary carcinoma, either IFN-γ or Th1-polarizing anti-HER2 vaccination, when administered with anti-HER2 antibodies, demonstrated increased intratumor CUL5 expression, decreased surface HER2, and tumor senescence with significant therapeutic activity. IFN-γ synergized with multiple HER2-targeted agents to decrease surface HER2 expression, resulting in decreased tumor growth. These data suggest a novel function of IFN-γ that regulates HER2 through the PDP pathway and provides an opportunity to impact HER2 responses through anti-tumor immunity.
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http://dx.doi.org/10.1016/j.ymthe.2020.12.037DOI Listing
January 2021

Effects of checkpoint kinase 1 inhibition by prexasertib on the tumor immune microenvironment of head and neck squamous cell carcinoma.

Mol Carcinog 2021 02 30;60(2):138-150. Epub 2020 Dec 30.

Department of Head and Neck-Endocrine Oncology, Moffitt Cancer Center, Tampa, Florida, USA.

Prognosis for patients with recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC) remains poor. Development of more effective and less toxic targeted therapies is necessary for HNSCC patients. Checkpoint kinase 1 (CHK1) plays a vital role in cell cycle regulation and is a promising therapeutic target in HNSCC. Prexasertib, a CHK1 inhibitor, induces DNA damage and cell death, however, its effect on the tumor immune microenvironment (TIME) is largely unknown. Therefore, we evaluated a short-term and long-term effects of prexasertib in HNSCC and its TIME. Prexasertib caused increased DNA damage and cell death in vitro and significant tumor regression and improved survival in vivo. The gene expression and multiplex immunohistochemistry (mIHC) analyses of the in vivo tumors demonstrated increased expression of genes that are related to T-cell activation and increased immune cell trafficking, and decreased expression of genes that related to immunosuppression. However, increased expression of genes related to immunosuppression emerged over time suggesting evasion of immune surveillances. These findings in gene expression analyses were confirmed using mIHC which showed differential modulation of TIME in the tumor margins and as well as cores over time. These results suggest that evasion of immune surveillance, at least in part, may contribute to the acquired resistance to prexasertib in HNSCC.
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http://dx.doi.org/10.1002/mc.23275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856233PMC
February 2021

Methyltransferase inhibitors restore SATB1 protective activity against cutaneous T cell lymphoma in mice.

J Clin Invest 2021 Feb;131(3)

Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.

Cutaneous T cell lymphoma (CTCL) has a poorly understood etiology and no known cure. Using conditional knockout mice, we found that ablation of the genomic organizer special AT-rich sequence-binding protein 1 (Satb1) caused malignant transformation of mature, skin-homing, Notch-activated CD4+ and CD8+ T cells into progressively fatal lymphoma. Mechanistically, Satb1 restrained Stat5 phosphorylation and the expression of skin-homing chemokine receptors in mature T cells. Notably, methyltransferase-dependent epigenetic repression of SATB1 was universally found in human Sézary syndrome, but not in other peripheral T cell malignancies. H3K27 and H3K9 trimethylation occluded the SATB1 promoter in Sézary cells, while inhibition of SUV39H1/2 methyltransferases (unlike EZH2 inhibition) restored protective SATB1 expression and selectively abrogated the growth of primary Sézary cells more effectively than romidepsin. Therefore, inhibition of methyltransferases that silence SATB1 could address an unmet need for patients with mycosis fungoides/Sézary syndrome, a set of incurable diseases.
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http://dx.doi.org/10.1172/JCI135711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843215PMC
February 2021

Humoral immune responses: Unsung heroes of the war on cancer.

Semin Immunol 2020 06 9;49:101419. Epub 2020 Nov 9.

Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.

Solid cancers progress from primordial lesions through complex interactions between tumor-promoting and anti-tumor immune cell types, ultimately leading to the orchestration of humoral and T cell adaptive immune responses, albeit in an immunosuppressive environment. B cells infiltrating most established tumors have been associated with a dual role: Some studies have associated antibodies produced by tumor-associated B cells with the promotion of regulatory activities on myeloid cells, and also with direct immunosuppression through the production of IL-10, IL-35 or TGF-β. In contrast, recent studies in multiple human malignancies identify B cell responses with delayed malignant progression and coordinated T cell protective responses. This includes the elusive role of Tertiary Lymphoid Structures identified in many human tumors, where the function of B cells remains unknown. Here, we discuss emerging data on the dual role of B cell responses in the pathophysiology of human cancer, providing a perspective on future directions and possible novel interventions to restore the coordinated action of both branches of the adaptive immune response, with the goal of maximizing immunotherapeutic effectiveness.
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http://dx.doi.org/10.1016/j.smim.2020.101419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738315PMC
June 2020

Prospective Single-Arm Phase 1 and 2 Study: Ipilimumab and Nivolumab With Thoracic Radiation Therapy After Platinum Chemotherapy in Extensive-Stage Small Cell Lung Cancer.

Int J Radiat Oncol Biol Phys 2021 Feb 28;109(2):425-435. Epub 2020 Sep 28.

Department of Medical Oncology, Duke Cancer Institute, Duke University Medical Center.

Purpose: Consolidative thoracic radiation therapy (TRT) has been shown to improve outcomes for patients with extensive stage small cell lung cancer. We hypothesized that the addition of ipilimumab (IPI) and nivolumab (NIVO) after TRT would improve outcomes for patients with extensive stage small cell lung cancer.

Methods And Materials: Eligibility required stable disease or better after platinum doublet chemotherapy. Study therapy included consolidative TRT to 30 Gy in 10 fractions, targeting residual primary tumor and initially involved regional lymph nodes. Two weeks after TRT, patients received concurrent IPI (3 mg/kg) and NIVO (1 mg/kg) every 3 weeks for 4 doses followed by NIVO monotherapy (480 mg) every 4 weeks until progression or up to 1 year.

Results: The study enrolled 21 patients, with 6-month progression-free survival (PFS) of 24% (90% confidence interval [CI], 11%-40%) and a median PFS of 4.5 months (95% CI, 2.7%-4.6%). The 12-month overall survival (OS) was 48% (95% CI, 29%-64%) with a median OS of 11.7 months (95% CI, 4.7%-16.0%). Fifty-two percent of patients had ≥1 possibly related grade 3 to 4 immune-related adverse event. Grade 3 pulmonary and gastrointestinal immune-related adverse events were recorded in 19% and 24% of patients, respectively. Exploratory analysis showed increased cytotoxic T cell (CD3+CD8+) tumor infiltration was associated with favorable PFS (P = .01) and OS (P = .02). Reduction in peripheral blood CD3+CD8+ from baseline to after first dose of IPI/NIVO was associated with improved PFS (P = .02) and OS (P = .02).

Conclusions: Consolidative IPI and NIVO after platinum-based chemotherapy and TRT demonstrated a toxicity profile consistent with the known adverse events attributable to IPI and NIVO. Although the study regimen did not significantly improve PFS, the OS was higher than historic expectations. CD3+CD8+ tumor infiltration and migration may identify patients most likely to have improved outcomes in small cell lung cancer.
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http://dx.doi.org/10.1016/j.ijrobp.2020.09.031DOI Listing
February 2021

CD122-Selective IL2 Complexes Reduce Immunosuppression, Promote Treg Fragility, and Sensitize Tumor Response to PD-L1 Blockade.

Cancer Res 2020 11 18;80(22):5063-5075. Epub 2020 Sep 18.

Department of Medicine, University of Texas Health San Antonio, Texas.

The IL2 receptor (IL2R) is an attractive cancer immunotherapy target that controls immunosuppressive T regulatory cells (Treg) and antitumor T cells. Here we used IL2Rβ-selective IL2/anti-IL2 complexes (IL2c) to stimulate effector T cells preferentially in the orthotopic mouse ID8agg ovarian cancer model. Despite strong tumor rejection, IL2c unexpectedly lowered the tumor microenvironmental CD8/Treg ratio. IL2c reduced tumor microenvironmental Treg suppression and induced a fragile Treg phenotype, helping explain improved efficacy despite numerically increased Tregs without affecting Treg in draining lymph nodes. IL2c also reduced Treg-mediated, high-affinity IL2R signaling needed for optimal Treg functions, a likely mechanism for reduced Treg suppression. Effector T-cell IL2R signaling was simultaneously improved, suggesting that IL2c inhibits Treg functions without hindering effector T cells, a limitation of most Treg depletion agents. Anti-PD-L1 antibody did not treat ID8agg, but adding IL2c generated complete tumor regressions and protective immune memory not achieved by either monotherapy. Similar anti-PD-L1 augmentation of IL2c and degradation of Treg functions were seen in subcutaneous B16 melanoma. Thus, IL2c is a multifunctional immunotherapy agent that stimulates immunity, reduces immunosuppression in a site-specific manner, and combines with other immunotherapies to treat distinct tumors in distinct anatomic compartments. SIGNIFICANCE: These findings present CD122-targeted IL2 complexes as an advancement in cancer immunotherapy, as they reduce Treg immunosuppression, improve anticancer immunity, and boost PD-L1 immune checkpoint blockade efficacy in distinct tumors and anatomic locations.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-0002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669742PMC
November 2020

BTN3A1 governs antitumor responses by coordinating αβ and γδ T cells.

Science 2020 08;369(6506):942-949

Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.

Gamma delta (γδ) T cells infiltrate most human tumors, but current immunotherapies fail to exploit their in situ major histocompatibility complex-independent tumoricidal potential. Activation of γδ T cells can be elicited by butyrophilin and butyrophilin-like molecules that are structurally similar to the immunosuppressive B7 family members, yet how they regulate and coordinate αβ and γδ T cell responses remains unknown. Here, we report that the butyrophilin BTN3A1 inhibits tumor-reactive αβ T cell receptor activation by preventing segregation of N-glycosylated CD45 from the immune synapse. Notably, CD277-specific antibodies elicit coordinated restoration of αβ T cell effector activity and BTN2A1-dependent γδ lymphocyte cytotoxicity against BTN3A1 cancer cells, abrogating malignant progression. Targeting BTN3A1 therefore orchestrates cooperative killing of established tumors by αβ and γδ T cells and may present a treatment strategy for tumors resistant to existing immunotherapies.
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http://dx.doi.org/10.1126/science.aay2767DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7646930PMC
August 2020

Sirt2 Inhibition Enhances Metabolic Fitness and Effector Functions of Tumor-Reactive T Cells.

Cell Metab 2020 Sep 7;32(3):420-436.e12. Epub 2020 Aug 7.

Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA; Department of Radiation Oncology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA. Electronic address:

Dysregulated metabolism is a key driver of maladaptive tumor-reactive T lymphocytes within the tumor microenvironment. Actionable targets that rescue the effector activity of antitumor T cells remain elusive. Here, we report that the Sirtuin-2 (Sirt2) NAD-dependent deacetylase inhibits T cell metabolism and impairs T cell effector functions. Remarkably, upregulation of Sirt2 in human tumor-infiltrating lymphocytes (TILs) negatively correlates with response to TIL therapy in advanced non-small-cell lung cancer. Mechanistically, Sirt2 suppresses T cell metabolism by targeting key enzymes involved in glycolysis, tricarboxylic acid-cycle, fatty acid oxidation, and glutaminolysis. Accordingly, Sirt2-deficient murine T cells exhibit increased glycolysis and oxidative phosphorylation, resulting in enhanced proliferation and effector functions and subsequently exhibiting superior antitumor activity. Importantly, pharmacologic inhibition of Sirt2 endows human TILs with these superior metabolic fitness and effector functions. Our findings unveil Sirt2 as an unexpected actionable target for reprogramming T cell metabolism to augment a broad spectrum of cancer immunotherapies.
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http://dx.doi.org/10.1016/j.cmet.2020.07.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484212PMC
September 2020

The Association of Mutation with Tumor Mutation Burden and Its Prognostic Implications in Cutaneous Melanoma.

Cancer Epidemiol Biomarkers Prev 2020 Sep 1;29(9):1792-1799. Epub 2020 Jul 1.

Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.

Background: is a mucin marker that is frequently mutated in melanoma, but whether mutations could be useful as a surrogate biomarker for tumor mutation burden (TMB) remains unclear.

Methods: This study rigorously evaluates the mutation as a clinical biomarker in cutaneous melanoma by utilizing genomic and clinical data from patient samples from The Cancer Genome Atlas (TCGA) and two independent validation cohorts. We further extended the analysis to studies with patients treated with immunotherapies.

Results: Analysis results showed that samples with mutations had a higher TMB than the samples of wild-type, with strong statistical significance ( < 0.001) in all melanoma cohorts tested. Associations between mutations and TMB remained statistically significant after adjusting for potential confounding factors in the TCGA cohort [OR, 9.28 (95% confidence interval (CI), 5.18-17.39); < 0.001], Moffitt cohort [OR, 31.95 (95% CI, 8.71-163.90); < 0.001], and Yale cohort [OR, 8.09 (95% CI, 3.12-23.79); < 0.01]. mutations were also found to be associated with overall survival in the TCGA [HR, 0.62; (95% CI, 0.45-0.85); < 0.01] and Moffitt cohorts [HR, 0.49 (95% CI, 0.28-0.87); = 0.014]. Strikingly, is the only top frequently mutated gene for which prognostic significance was observed. mutations were also found valuable in predicting anti-CTLA-4 and anti-PD-1 therapy responses.

Conclusions: mutation appears to be a useful predictive marker of global TMB and patient survival in melanoma.

Impact: This is, to the best of our knowledge, the first systematic evaluation of mutation as a clinical biomarker and a predictive biomarker for immunotherapy in melanoma.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483810PMC
September 2020

Kindlin-3 gives patrolling monocytes a strong grip.

J Leukoc Biol 2020 06;107(6):879-881

Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.

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http://dx.doi.org/10.1002/JLB.3CE0320-168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7374932PMC
June 2020

Loss of microRNA-21 leads to profound stromal remodeling and short survival in K-Ras-driven mouse models of pancreatic cancer.

Int J Cancer 2020 Oct 26;147(8):2265-2278. Epub 2020 May 26.

Precision Health Program, Michigan State University, East Lansing, Michigan, USA.

The microenvironment of pancreatic cancer adenocarcinoma (PDAC) is highly desmoplastic with distinct tumor-restraining and tumor-promoting fibroblast subpopulations. Re-education rather than indiscriminate elimination of these fibroblasts has emerged as a new strategy for combination therapy. Here, we studied the effects of global loss of profibrotic noncoding regulatory microRNA-21 (miR-21) in K-Ras-driven p53-deleted genetically engineered mouse models of PDAC. Strikingly, loss of miR-21 accelerated tumor initiation via mucinous cystic neoplastic lesions and progression to locally advanced invasive carcinoma from which animals precipitously succumbed at an early age. The absence of tumor-restraining myofibroblasts and a massive infiltrate of immune cells were salient phenotypic features of global miR-21 loss. Stromal miR-21 activity was required for induction of tumor-restraining myofibroblasts in in vivo isograft transplantation experiments. Low miR-21 expression negatively correlated with a fibroblast gene expression signature and positively with an immune cell gene expression signature in The Cancer Genome Atlas PDAC data set (n = 156) mirroring findings in the mouse models. Our results exposed an overall tumor-suppressive function of miR-21 in in vivo PDAC models. These results have important clinical implications for anti-miR-21-based inhibitory therapeutic approaches under consideration for PDAC and other cancer types. Mechanistic dissection of the cell-intrinsic role of miR-21 in cancer-associated fibroblasts and other cell types will be needed to inform best strategies for pharmacological modulation of miR-21 activity to remodel the tumor microenvironment and enhance treatment response in PDAC.
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http://dx.doi.org/10.1002/ijc.33041DOI Listing
October 2020

The Unfolded Protein Response Mediator PERK Governs Myeloid Cell-Driven Immunosuppression in Tumors through Inhibition of STING Signaling.

Immunity 2020 04;52(4):668-682.e7

Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. Electronic address:

The primary mechanisms supporting immunoregulatory polarization of myeloid cells upon infiltration into tumors remain largely unexplored. Elucidation of these signals could enable better strategies to restore protective anti-tumor immunity. Here, we investigated the role of the intrinsic activation of the PKR-like endoplasmic reticulum (ER) kinase (PERK) in the immunoinhibitory actions of tumor-associated myeloid-derived suppressor cells (tumor-MDSCs). PERK signaling increased in tumor-MDSCs, and its deletion transformed MDSCs into myeloid cells that activated CD8 T cell-mediated immunity against cancer. Tumor-MDSCs lacking PERK exhibited disrupted NRF2-driven antioxidant capacity and impaired mitochondrial respiratory homeostasis. Moreover, reduced NRF2 signaling in PERK-deficient MDSCs elicited cytosolic mitochondrial DNA elevation and, consequently, STING-dependent expression of anti-tumor type I interferon. Reactivation of NRF2 signaling, conditional deletion of STING, or blockade of type I interferon receptor I restored the immunoinhibitory potential of PERK-ablated MDSCs. Our findings demonstrate the pivotal role of PERK in tumor-MDSC functionality and unveil strategies to reprogram immunosuppressive myelopoiesis in tumors to boost cancer immunotherapy.
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http://dx.doi.org/10.1016/j.immuni.2020.03.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7207019PMC
April 2020

c-Maf: a bad influence in the education of macrophages.

J Clin Invest 2020 04;130(4):1629-1631

Tumor-associated macrophages (TAMs) represent the most abundant hematopoietic cell type in the solid tumor microenvironment. TAMs drive T cell inhibition, promote angiogenesis, and produce tumor growth factors. Although they can paradoxically exert antitumor activity and prime protective immunity, the pathways driving this phenotype remain unclear. In this issue of the JCI, Liu and colleagues identified the c-Maf transcription factor as a master regulator of protumoral TAM polarization. The authors found that c-Maf promoted TAMs' immunosuppressive activity, governed their metabolic programming, and drove expression of the macrophage differentiation protein, CSF1R. Further, inhibiting c-Maf in myeloid progenitors, and consequent myeloid-lineage cells, including TAMs, delayed tumor growth. Importantly, β-glucan treatment reduced c-MAF expression in macrophages and monocytes from patients with non-small cell lung cancer (NSCLC) where c-MAF is overexpressed. These results reveal mechanisms whereby myeloid cells drive human cancer progression by thwarting protective immunity and could lead to immunotherapy for most solid malignancies.
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http://dx.doi.org/10.1172/JCI135444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7108897PMC
April 2020

Exosomes Produced by Mesenchymal Stem Cells Drive Differentiation of Myeloid Cells into Immunosuppressive M2-Polarized Macrophages in Breast Cancer.

J Immunol 2019 12 8;203(12):3447-3460. Epub 2019 Nov 8.

Immunology Laboratory, Department of Zoology, University of Calcutta, Kolkata 700019, India;

Tumor-associated macrophages are major contributors to malignant progression and resistance to immunotherapy, but the mechanisms governing their differentiation from immature myeloid precursors remain incompletely understood. In this study, we demonstrate that exosomes secreted by human and mouse tumor-educated mesenchymal stem cells (MSCs) drive accelerated breast cancer progression by inducing differentiation of monocytic myeloid-derived suppressor cells into highly immunosuppressive M2-polarized macrophages at tumor beds. Mechanistically, MSC-derived exosomes but not exosomes from tumor cells contain TGF-β, C1q, and semaphorins, which promote myeloid tolerogenic activity by driving PD-L1 overexpression in both immature myelomonocytic precursors and committed CD206 macrophages and by inducing differentiation of MHC class II macrophages with enhanced l-Arginase activity and IL-10 secretion at tumor beds. Accordingly, administration of tumor-associated murine MSC-derived exosomes accelerates tumor growth by dampening antitumor immunity, and macrophage depletion eliminates exosome-dependent differences in malignant progression. Our results unveil a new role for MSC-derived exosomes in the differentiation of myeloid-derived suppressor cells into macrophages, which governs malignant growth.
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http://dx.doi.org/10.4049/jimmunol.1900692DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6994919PMC
December 2019

AMPK Alpha-1 Intrinsically Regulates the Function and Differentiation of Tumor Myeloid-Derived Suppressor Cells.

Cancer Res 2019 10 13;79(19):5034-5047. Epub 2019 Aug 13.

Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.

Myeloid-derived suppressor cells (MDSC) represent a primary mechanism of immune evasion in tumors and have emerged as a major obstacle for cancer immunotherapy. The immunoinhibitory activity of MDSC is tightly regulated by the tumor microenvironment and occurs through mechanistic mediators that remain unclear. Here, we elucidated the intrinsic interaction between the expression of AMP-activated protein kinase alpha (AMPKα) and the immunoregulatory activity of MDSC in tumors. AMPKα signaling was increased in tumor-MDSC from tumor-bearing mice and patients with ovarian cancer. Transcription of the Ampkα1-coding gene, , in tumor-MDSC was induced by cancer cell-derived granulocyte-monocyte colony-stimulating factor (GM-CSF) and occurred in a Stat5-dependent manner. Conditional deletion of in myeloid cells, or therapeutic inhibition of Ampkα in tumor-bearing mice, delayed tumor growth, inhibited the immunosuppressive potential of MDSC, triggered antitumor CD8 T-cell immunity, and boosted the efficacy of T-cell immunotherapy. Complementarily, therapeutic stimulation of AMPKα signaling intrinsically promoted MDSC immunoregulatory activity. In addition, deletion antagonized the differentiation of monocytic-MDSC (M-MDSC) to macrophages and re-routed M-MDSC, but not granulocytic-MDSC (PMN-MDSC), into cells that elicited direct antitumor cytotoxic effects through nitric oxide synthase 2-mediated actions. Thus, our results demonstrate the primary role of AMPKα1 in the immunosuppressive effects induced by tumor-MDSC and support the therapeutic use of AMPK inhibitors to overcome MDSC-induced T-cell dysfunction in cancer. SIGNIFICANCE: AMPKα1 regulates the immunosuppressive activity and differentiation of tumor-MDSC, suggesting AMPK inhibition as a potential therapeutic strategy to restore protective myelopoiesis in cancer.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-0880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774829PMC
October 2019

Breaking barriers for T cells by targeting the EPHA2/TGF-β/COX-2 axis in pancreatic cancer.

J Clin Invest 2019 07 29;129(9):3521-3523. Epub 2019 Jul 29.

Pancreatic ductal adenocarcinoma is projected to become the second leading cause of cancer-related death and is largely resistant to immunotherapies. The tumor microenvironment, largely composed of heterogeneous myeloid cells, creates a physical, metabolic, and immunosuppressive barrier that prevents T cells from infiltrating cancer beds. In this issue of the JCI, Markosyan and colleagues have reported a tumor-intrinsic mechanism that excludes T cells from the vicinity of tumor cells. They showed that a receptor tyrosine kinase, ephrin-A receptor 2 (EPHA2), regulates prostaglandin endoperoxide synthase 2 (PTGS2) (encodes COX-2) expression in a TGF-β signaling-dependent manner. Genetic ablation of Epha2 or Ptgs2 in preclinical models or pharmacological inhibition of COX-2 elicited the transformation of this immunosuppressive microenvironment into a T cell-permissive milieu. Consequent T cell relocation rendered this immunoresistant malignancy responsive to combinations of checkpoint blockers and CD40 agonists. Because the association between T cell infiltration and the EPHA2/TGF-β/COX-2 axis is supported by independent clinical data, these results provide a rationale for ensuing clinical trials aimed at incorporating pancreatic cancer into the range of immunotherapy-responsive tumors.
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http://dx.doi.org/10.1172/JCI130316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6715408PMC
July 2019

Estimation of immune cell content in tumor using single-cell RNA-seq reference data.

BMC Cancer 2019 Jul 19;19(1):715. Epub 2019 Jul 19.

Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA.

Background: The rapid development of single-cell RNA sequencing (scRNA-seq) provides unprecedented opportunities to study the tumor ecosystem that involves a heterogeneous mixture of cell types. However, the majority of previous and current studies related to translational and molecular oncology have only focused on the bulk tumor and there is a wealth of gene expression data accumulated with matched clinical outcomes.

Results: In this paper, we introduce a scheme for characterizing cell compositions from bulk tumor gene expression by integrating signatures learned from scRNA-seq data. We derived the reference expression matrix to each cell type based on cell subpopulations identified in head and neck cancer dataset. Our results suggest that scRNA-Seq-derived reference matrix outperforms the existing gene panel and reference matrix with respect to distinguishing immune cell subtypes.

Conclusions: Findings and resources created from this study enable future and secondary analysis of tumor RNA mixtures in head and neck cancer for a more accurate cellular deconvolution, and can facilitate the profiling of the immune infiltration in other solid tumors due to the expression homogeneity observed in immune cells.
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http://dx.doi.org/10.1186/s12885-019-5927-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642583PMC
July 2019

PD-L1 Expression Correlates With Young Age and CD8+ TIL Density in Poorly Differentiated Cervical Squamous Cell Carcinoma.

Int J Gynecol Pathol 2020 Sep;39(5):428-435

Management options are limited in advanced or recurrent cervical carcinoma. The Food and Drug Administration has recently approved programed cell death-1 (PD-1)/PD-ligand-1 (PD-L1) inhibitors for the treatment of advanced PD-L1 positive cervical cancer. We studied PD-L1 expression in cervical squamous cell carcinoma (CSCC) samples initially on a The tissue microarray and then in full-tissue sections from poorly differentiated (grade 3) cancers. Tissue microarray was composed of 45 grade 3 and 2 (moderately differentiated) tumors. PD-L1 expression was evaluated as categorical data and by obtaining combined positive score of neoplastic and mononuclear inflammatory cells. In tissue microarray samples PD-L1 expression was higher in poorly differentiated cancers compared with grade 2 tumors by immunohistochemistry. Full-tissue sections from grade 3 CSCC (n=22) were stained with PD-L1, CD8, and VEGF antibodies. Poorly differentiated CSCC samples had diffuse (≥50%) and focal/patchy staining patterns. The latter pattern showed localized tumor-stroma interface staining in 5 samples with low combined positive score. Importantly, younger patients (median=36) had tumors with higher expression. PD-L1 expression was associated with larger tumor size and absent lymphovascular invasion. In addition, CD8 tumor-infiltrating lymphocyte density within the neoplastic tissue matched with PD-L1 levels. The overall survival rates did not correlate with PD-L1 expression. However, in early-stage disease high CD8 tumor-infiltrating lymphocyte density within the peritumoral stroma was associated with better survival outcomes in multivariate analysis. PD-L1 expression and CD8 tumor-infiltrating lymphocyte density may be useful to define a subgroup of patients with relatively better prognosis in poorly differentiated CSCC. It is warranted to validate our results in a larger sample size.
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http://dx.doi.org/10.1097/PGP.0000000000000623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7010346PMC
September 2020

Illuminating the Numbers: Integrating Mathematical Models to Optimize Photomedicine Dosimetry and Combination Therapies.

Front Phys 2019 Apr 2;7. Epub 2019 Apr 2.

Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, United States.

Cancer photomedicine offers unique mechanisms for inducing local tumor damage with the potential to stimulate local and systemic anti-tumor immunity. Optically-active nanomedicine offers these features as well as spatiotemporal control of tumor-focused drug release to realize synergistic combination therapies. Achieving quantitative dosimetry is a major challenge, and dosimetry is fundamental to photomedicine for personalizing and tailoring therapeutic regimens to specific patients and anatomical locations. The challenge of dosimetry is perhaps greater for photomedicine than many standard therapies given the complexity of light delivery and light-tissue interactions as well as the resulting photochemistry responsible for tumor damage and drug-release, in addition to the usual intricacies of therapeutic agent delivery. An emerging multidisciplinary approach in oncology utilizes mathematical and computational models to iteratively and quantitively analyze complex dosimetry, and biological response parameters. These models are parameterized by preclinical and clinical observations and then tested against previously unseen data. Such calibrated and validated models can be deployed to simulate treatment doses, protocols, and combinations that have not yet been experimentally or clinically evaluated and can provide testable optimal treatment outcomes in a practical workflow. Here, we foresee the utility of these computational approaches to guide adaptive therapy, and how mathematical models might be further developed and integrated as a novel methodology to guide precision photomedicine.
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http://dx.doi.org/10.3389/fphy.2019.00046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6529192PMC
April 2019

ER stress-induced mediator C/EBP homologous protein thwarts effector T cell activity in tumors through T-bet repression.

Nat Commun 2019 03 20;10(1):1280. Epub 2019 Mar 20.

Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, 33612, USA.

Understanding the intrinsic mediators that render CD8 T cells dysfunctional in the tumor microenvironment is a requirement to develop more effective cancer immunotherapies. Here, we report that C/EBP homologous protein (Chop), a downstream sensor of severe endoplasmic reticulum (ER) stress, is a major negative regulator of the effector function of tumor-reactive CD8 T cells. Chop expression is increased in tumor-infiltrating CD8 T cells, which correlates with poor clinical outcome in ovarian cancer patients. Deletion of Chop in T cells improves spontaneous antitumor CD8 T cell immunity and boosts the efficacy of T cell-based immunotherapy. Mechanistically, Chop in CD8 T cells is elevated primarily through the ER stress-associated kinase Perk and a subsequent induction of Atf4; and directly represses the expression of T-bet, a master regulator of effector T cell function. These findings demonstrate the primary role of Chop in tumor-induced CD8 T cell dysfunction and the therapeutic potential of blocking Chop or ER stress to unleash T cell-mediated antitumor immunity.
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http://dx.doi.org/10.1038/s41467-019-09263-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6426975PMC
March 2019

Inhibition of Human Dendritic Cell ER Stress Response Reduces T Cell Alloreactivity Yet Spares Donor Anti-tumor Immunity.

Front Immunol 2018 6;9:2887. Epub 2018 Dec 6.

Department of Blood and Marrow Transplantation and Cellular Immunotherapy, Tampa, FL, United States.

Acute graft- vs. -host disease (GVHD) is an important cause of morbidity and death after allogeneic hematopoietic cell transplantation (HCT). We identify a new approach to prevent GVHD that impairs monocyte-derived dendritic cell (moDC) alloactivation of T cells, yet preserves graft- vs.-leukemia (GVL). Exceeding endoplasmic reticulum (ER) capacity results in a spliced form of X-box binding protein-1 (XBP-1s). XBP-1s mediates ER stress and inflammatory responses. We demonstrate that siRNA targeting XBP-1 in moDCs abrogates their stimulation of allogeneic T cells. B-I09, an inositol-requiring enzyme-1α (IRE1α) inhibitor that prevents XBP-1 splicing, reduces human moDC migration, allo-stimulatory potency, and curtails moDC IL-1β, TGFβ, and p40 cytokines, suppressing Th1 and Th17 cell priming. B-I09-treated moDCs reduce responder T cell activation via calcium flux without interfering with regulatory T cell (Treg) function or GVL effects by cytotoxic T lymphocytes (CTL) and NK cells. In a human T cell mediated xenogeneic GVHD model, B-I09 inhibition of XBP-1s reduced target-organ damage and pathogenic Th1 and Th17 cells without impacting donor Tregs or anti-tumor CTL. DC XBP-1s inhibition provides an innovative strategy to prevent GVHD and retain GVL.
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http://dx.doi.org/10.3389/fimmu.2018.02887DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6291501PMC
October 2019

IL-33 delays metastatic peritoneal cancer progression inducing an allergic microenvironment.

Oncoimmunology 2019;8(1):e1515058. Epub 2018 Sep 6.

Vaccine and Immunotherapy Center, The Wistar Institute, Philadlephia, PA, USA.

Ovarian cancer is frequently diagnosed as peritoneal carcinomatosis. Unlike other tumor locations, the peritoneal cavity is commonly exposed to gut-breaching and ascending genital microorganisms and has a unique immune environment. IL-33 is a local cytokine that can activate innate and adaptive immunity. We studied the effectiveness of local IL-33 delivery in the treatment of cancer that has metastasized to the peritoneal cavity. Direct peritoneal administration of IL-33 delayed the progression of metastatic peritoneal cancer. Prolongation in survival was not associated with a direct effect of IL-33 on tumor cells, but with major changes in the immune microenvironment of the tumor. IL-33 promoted a significant increase in the leukocyte compartment of the tumor immunoenvironment and an allergic cytokine profile. We observed a substantial increase in the number of activated CD4 T-cells accompanied by peritoneal eosinophil infiltration, B-cell activation and activation of peritoneal macrophages which displayed tumoricidal capacity. Depletion of CD4 cells, eosinophils or macrophages reduced the anti-tumor effects of IL-33 but none of these alone were sufficient to completely abrogate its positive benefit. In conclusion, local administration of IL-33 generates an allergic tumor environment resulting in a novel approach for treatment of metastatic peritoneal malignancies, such as advanced ovarian cancer.
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http://dx.doi.org/10.1080/2162402X.2018.1515058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287802PMC
September 2018

Dysregulated Microbial Fermentation of Soluble Fiber Induces Cholestatic Liver Cancer.

Cell 2018 10;175(3):679-694.e22

UT-Microbiome Consortium, Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA; Department of Medical Microbiology and Immunology, University of Toledo, Toledo, OH 43614, USA. Electronic address:

Dietary soluble fibers are fermented by gut bacteria into short-chain fatty acids (SCFA), which are considered broadly health-promoting. Accordingly, consumption of such fibers ameliorates metabolic syndrome. However, incorporating soluble fiber inulin, but not insoluble fiber, into a compositionally defined diet, induced icteric hepatocellular carcinoma (HCC). Such HCC was microbiota-dependent and observed in multiple strains of dysbiotic mice but not in germ-free nor antibiotics-treated mice. Furthermore, consumption of an inulin-enriched high-fat diet induced both dysbiosis and HCC in wild-type (WT) mice. Inulin-induced HCC progressed via early onset of cholestasis, hepatocyte death, followed by neutrophilic inflammation in liver. Pharmacologic inhibition of fermentation or depletion of fermenting bacteria markedly reduced intestinal SCFA and prevented HCC. Intervening with cholestyramine to prevent reabsorption of bile acids also conferred protection against such HCC. Thus, its benefits notwithstanding, enrichment of foods with fermentable fiber should be approached with great caution as it may increase risk of HCC.
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http://dx.doi.org/10.1016/j.cell.2018.09.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6232850PMC
October 2018

IRE1α-XBP1 controls T cell function in ovarian cancer by regulating mitochondrial activity.

Nature 2018 10 10;562(7727):423-428. Epub 2018 Oct 10.

Weill Cornell Graduate School of Medical Sciences, New York, NY, USA.

Tumours evade immune control by creating hostile microenvironments that perturb T cell metabolism and effector function. However, it remains unclear how intra-tumoral T cells integrate and interpret metabolic stress signals. Here we report that ovarian cancer-an aggressive malignancy that is refractory to standard treatments and current immunotherapies-induces endoplasmic reticulum stress and activates the IRE1α-XBP1 arm of the unfolded protein response in T cells to control their mitochondrial respiration and anti-tumour function. In T cells isolated from specimens collected from patients with ovarian cancer, upregulation of XBP1 was associated with decreased infiltration of T cells into tumours and with reduced IFNG mRNA expression. Malignant ascites fluid obtained from patients with ovarian cancer inhibited glucose uptake and caused N-linked protein glycosylation defects in T cells, which triggered IRE1α-XBP1 activation that suppressed mitochondrial activity and IFNγ production. Mechanistically, induction of XBP1 regulated the abundance of glutamine carriers and thus limited the influx of glutamine that is necessary to sustain mitochondrial respiration in T cells under glucose-deprived conditions. Restoring N-linked protein glycosylation, abrogating IRE1α-XBP1 activation or enforcing expression of glutamine transporters enhanced mitochondrial respiration in human T cells exposed to ovarian cancer ascites. XBP1-deficient T cells in the metastatic ovarian cancer milieu exhibited global transcriptional reprogramming and improved effector capacity. Accordingly, mice that bear ovarian cancer and lack XBP1 selectively in T cells demonstrate superior anti-tumour immunity, delayed malignant progression and increased overall survival. Controlling endoplasmic reticulum stress or targeting IRE1α-XBP1 signalling may help to restore the metabolic fitness and anti-tumour capacity of T cells in cancer hosts.
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http://dx.doi.org/10.1038/s41586-018-0597-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6237282PMC
October 2018

Age Correlates with Response to Anti-PD1, Reflecting Age-Related Differences in Intratumoral Effector and Regulatory T-Cell Populations.

Clin Cancer Res 2018 11 13;24(21):5347-5356. Epub 2018 Jun 13.

The Wistar Institute, Philadelphia, Philadelphia.

We have shown that the aged microenvironment increases melanoma metastasis, and decreases response to targeted therapy, and here we queried response to anti-PD1. We analyzed the relationship between age, response to anti-PD1, and prior therapy in 538 patients. We used mouse models of melanoma, to analyze the intratumoral immune microenvironment in young versus aged mice and confirmed our findings in human melanoma biopsies. Patients over the age of 60 responded more efficiently to anti-PD-1, and likelihood of response to anti-PD-1 increased with age, even when we controlled for prior MAPKi therapy. Placing genetically identical tumors in aged mice (52 weeks) significantly increased their response to anti-PD1 as compared with the same tumors in young mice (8 weeks). These data suggest that this increased response in aged patients occurs even in the absence of a more complex mutational landscape. Next, we found that young mice had a significantly higher population of regulatory T cells (Tregs), skewing the CD8:Treg ratio. FOXP3 staining of human melanoma biopsies revealed similar increases in Tregs in young patients. Depletion of Tregs using anti-CD25 increased the response to anti-PD1 in young mice. While there are obvious limitations to our study, including our inability to conduct a meta-analysis due to a lack of available data, and our inability to control for mutational burden, there is a remarkable consistency in these data from over 500 patients across 8 different institutes worldwide. These results stress the importance of considering age as a factor for immunotherapy response. .
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http://dx.doi.org/10.1158/1078-0432.CCR-18-1116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6324578PMC
November 2018

Repurposing Pan-HDAC Inhibitors for ARID1A-Mutated Ovarian Cancer.

Cell Rep 2018 03;22(13):3393-3400

Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA. Electronic address:

ARID1A, a subunit of the SWI/SNF complex, is among the most frequently mutated genes across cancer types. ARID1A is mutated in more than 50% of ovarian clear cell carcinomas (OCCCs), diseases that have no effective therapy. Here, we show that ARID1A mutation confers sensitivity to pan-HDAC inhibitors such as SAHA in ovarian cancers. This correlated with enhanced growth suppression induced by the inhibition of HDAC2 activity in ARID1A-mutated cells. HDAC2 interacts with EZH2 in an ARID1A status-dependent manner. HDAC2 functions as a co-repressor of EZH2 to suppress the expression of EZH2/ARID1A target tumor suppressor genes such as PIK3IP1 to inhibit proliferation and promote apoptosis. SAHA reduced the growth and ascites of the ARID1A-inactivated OCCCs in both orthotopic and genetic mouse models. This correlated with a significant improvement of survival of mice bearing ARID1A-mutated OCCCs. These findings provided preclinical rationales for repurposing FDA-approved pan-HDAC inhibitors for treating ARID1A-mutated cancers.
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http://dx.doi.org/10.1016/j.celrep.2018.03.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5903572PMC
March 2018