Publications by authors named "Peter P Lee"

101 Publications

Clinical Response to Immunotherapy Targeting Programmed Cell Death Receptor 1/Programmed Cell Death Ligand 1 in Patients With Treatment-Resistant Microsatellite Stable Colorectal Cancer With and Without Liver Metastases.

JAMA Netw Open 2021 Aug 2;4(8):e2118416. Epub 2021 Aug 2.

Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, California.

Importance: Microsatellite stable (MSS) metastatic colorectal cancer has been historically characterized as resistant to immunotherapy. Recent studies have demonstrated limited clinical activity of programmed cell death receptor 1/programmed death ligand 1 (PD-1/PD-L1) targeting in MSS metastatic colorectal cancer. The association of metastatic disease in the liver with treatment response has not been fully investigated.

Objective: To investigate the association of liver metastases with response to PD-1/PD-L1-targeting therapy in MSS metastatic colorectal cancer.

Design, Setting, And Participants: This single-center retrospective cohort study evaluated clinical responses to PD-1- or PD-L1-targeting therapy, with or without other investigational agents, in patients with MSS metastatic colorectal cancer and disease progression after standard of care therapy from January 1, 2014, to December 31, 2020.

Main Outcomes And Measures: Objective response rate (ORR) and progression-free survival (PFS), measured from initiation of PD-1/PD-L1-targeting therapy.

Results: Ninety-five patients with MSS metastatic colorectal cancer were identified (54 men [56.8%]; median age, 55 [interquartile range (IQR), 49-64] years). The overall ORR was 8.4% (8 of 95 patients). Eight of 41 patients without liver metastases achieved an ORR of 19.5%, and no response was observed in 54 patients with liver metastases. The disease control rate was 58.5% (24 of 41) in patients without liver metastasis and 1.9% (1 of 54) in patients with liver metastasis. Patients without liver metastases at the time of PD-1/PD-L1-targeting treatment had a superior median PFS compared with patients with liver metastases (4.0 [IQR, 2.0-7.5] vs 1.5 [IQR, 1.0-2.0] months; P < .001). In addition, median PFS was 5.5 (IQR, 2.0-11.5) months for patients without any prior or current liver involvement at the time of PD-1/PD-L1-targeting treatment initiation. Using a multivariate Cox regression model correcting for Eastern Cooperative Oncology Group status, primary tumor location, RAS and BRAF status, tumor mutation burden, and metastatic sites, liver metastases was the variable with the most significant association with faster progression after PD-1/PD-L1 treatment inhibition (hazard ratio, 7.00; 95% CI, 3.18-15.42; P < .001).

Conclusions And Relevance: Findings of this cohort study suggest that patients with MSS metastatic colorectal cancer and without liver metastases may derive clinical benefits from checkpoint inhibitors, whereas the presence of liver metastases was associated with resistance. Further prospective studies are needed to investigate PD-1/PD-L1 inhibitors in patients with MSS metastatic colorectal cancer without liver metastases.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.18416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8353537PMC
August 2021

Spatial distribution of B cells and lymphocyte clusters as a predictor of triple-negative breast cancer outcome.

NPJ Breast Cancer 2021 Jul 1;7(1):84. Epub 2021 Jul 1.

Department of Physics and Astronomy, University of California, Irvine, Irvine, CA, USA.

While tumor infiltration by CD8 T cells is now widely accepted to predict outcomes, the clinical significance of intratumoral B cells is less clear. We hypothesized that spatial distribution rather than density of B cells within tumors may provide prognostic significance. We developed statistical techniques (fractal dimension differences and a box-counting method 'occupancy') to analyze the spatial distribution of tumor-infiltrating lymphocytes (TILs) in human triple-negative breast cancer (TNBC). Our results indicate that B cells in good outcome tumors (no recurrence within 5 years) are spatially dispersed, while B cells in poor outcome tumors (recurrence within 3 years) are more confined. While most TILs are located within the stroma, increased numbers of spatially dispersed lymphocytes within cancer cell islands are associated with a good prognosis. B cells and T cells often form lymphocyte clusters (LCs) identified via density-based clustering. LCs consist either of T cells only or heterotypic mixtures of B and T cells. Pure B cell LCs were negligible in number. Compared to tertiary lymphoid structures (TLS), LCs have fewer lymphocytes at lower densities. Both types of LCs are more abundant and more spatially dispersed in good outcomes compared to poor outcome tumors. Heterotypic LCs in good outcome tumors are smaller and more numerous compared to poor outcome. Heterotypic LCs are also closer to cancer islands in a good outcome, with LC size decreasing as they get closer to cancer cell islands. These results illuminate the significance of the spatial distribution of B cells and LCs within tumors.
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http://dx.doi.org/10.1038/s41523-021-00291-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249408PMC
July 2021

Ivermectin converts cold tumors hot and synergizes with immune checkpoint blockade for treatment of breast cancer.

NPJ Breast Cancer 2021 Mar 2;7(1):22. Epub 2021 Mar 2.

Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA, USA.

We show that treatment with the FDA-approved anti-parasitic drug ivermectin induces immunogenic cancer cell death (ICD) and robust T cell infiltration into breast tumors. As an allosteric modulator of the ATP/P2X4/P2X7 axis which operates in both cancer and immune cells, ivermectin also selectively targets immunosuppressive populations including myeloid cells and Tregs, resulting in enhanced Teff/Tregs ratio. While neither agent alone showed efficacy in vivo, combination therapy with ivermectin and checkpoint inhibitor anti-PD1 antibody achieved synergy in limiting tumor growth (p = 0.03) and promoted complete responses (p < 0.01), also leading to immunity against contralateral re-challenge with demonstrated anti-tumor immune responses. Going beyond primary tumors, this combination achieved significant reduction in relapse after neoadjuvant (p = 0.03) and adjuvant treatment (p < 0.001), and potential cures in metastatic disease (p < 0.001). Statistical modeling confirmed bona fide synergistic activity in both the adjuvant (p = 0.007) and metastatic settings (p < 0.001). Ivermectin has dual immunomodulatory and ICD-inducing effects in breast cancer, converting cold tumors hot, thus represents a rational mechanistic partner with checkpoint blockade.
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http://dx.doi.org/10.1038/s41523-021-00229-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925581PMC
March 2021

Dissecting Response to Cancer Immunotherapy by Applying Bayesian Network Analysis to Flow Cytometry Data.

Int J Mol Sci 2021 Feb 26;22(5). Epub 2021 Feb 26.

City of Hope National Medical Center, Department of Immuno-Oncology, Beckman Research Institute, 1500 East Duarte Road, Duarte, CA 91010, USA.

Cancer immunotherapy, specifically immune checkpoint blockade, has been found to be effective in the treatment of metastatic cancers. However, only a subset of patients achieve clinical responses. Elucidating pretreatment biomarkers predictive of sustained clinical response is a major research priority. Another research priority is evaluating changes in the immune system before and after treatment in responders vs. nonresponders. Our group has been studying immune networks as an accurate reflection of the global immune state. Flow cytometry (FACS, fluorescence-activated cell sorting) data characterizing immune cell panels in peripheral blood mononuclear cells (PBMC) from gastroesophageal adenocarcinoma (GEA) patients were used to analyze changes in immune networks in this setting. Here, we describe a novel computational pipeline to perform secondary analyses of FACS data using systems biology/machine learning techniques and concepts. The pipeline is centered around comparative Bayesian network analyses of immune networks and is capable of detecting strong signals that conventional methods (such as FlowJo manual gating) might miss. Future studies are planned to validate and follow up the immune biomarkers (and combinations/interactions thereof) associated with clinical responses identified with this computational pipeline.
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http://dx.doi.org/10.3390/ijms22052316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956201PMC
February 2021

Concepts and Applications of Information Theory to Immuno-Oncology.

Trends Cancer 2021 04 20;7(4):335-346. Epub 2021 Feb 20.

Division of Mathematical Oncology, Department of Computational and Quantitative Medicine, Beckman Research Institute of City of Hope, Duarte, CA, USA.

Recent successes of immune-modulating therapies for cancer have stimulated research on information flow within the immune system and, in turn, clinical applications of concepts from information theory. Through information theory, one can describe and formalize, in a mathematically rigorous fashion, the function of interconnected components of the immune system in health and disease. Specifically, using concepts including entropy, mutual information, and channel capacity, one can quantify the storage, transmission, encoding, and flow of information within and between cellular components of the immune system on multiple temporal and spatial scales. To understand, at the quantitative level, immune signaling function and dysfunction in cancer, we present a methodology-oriented review of information-theoretic treatment of biochemical signal transduction and transmission coupled with mathematical modeling.
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http://dx.doi.org/10.1016/j.trecan.2020.12.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8156485PMC
April 2021

Warburg Effect Is a Cancer Immune Evasion Mechanism Against Macrophage Immunosurveillance.

Front Immunol 2020 2;11:621757. Epub 2021 Feb 2.

Department of Immuno-Oncology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA, United States.

Evasion of immunosurveillance is critical for cancer initiation and development. The expression of "don't eat me" signals protects cancer cells from being phagocytosed by macrophages, and the blockade of such signals demonstrates therapeutic potential by restoring the susceptibility of cancer cells to macrophage-mediated phagocytosis. However, whether additional self-protective mechanisms play a role against macrophage surveillance remains unexplored. Here, we derived a macrophage-resistant cancer model from cells deficient in the expression of CD47, a major "don't eat me" signal, a macrophage selection assay. Comparative studies performed between the parental and resistant cells identified self-protective traits independent of CD47, which were examined with both pharmacological or genetic approaches in phagocytosis assays and tumor models for their roles in protecting against macrophage surveillance. Here we demonstrated that extracellular acidification resulting from glycolysis in cancer cells protected them against macrophage-mediated phagocytosis. The acidic tumor microenvironment resulted in direct inhibition of macrophage phagocytic ability and recruitment of weakly phagocytic macrophages. Targeting V-ATPase which transports excessive protons in cancer cells to acidify extracellular medium elicited a pro-phagocytic microenvironment with an increased ratio of M1-/M2-like macrophage populations, therefore inhibiting tumor development and metastasis. In addition, blockade of extracellular acidification enhanced cell surface exposure of CD71, targeting which by antibodies promoted cancer cell phagocytosis. Our results reveal that extracellular acidification due to the Warburg effect confers immune evasion ability on cancer cells. This previously unrecognized role highlights the components mediating the Warburg effect as potential targets for new immunotherapy harnessing the tumoricidal capabilities of macrophages.
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http://dx.doi.org/10.3389/fimmu.2020.621757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884830PMC
June 2021

A minimal model of T cell avidity may identify subtherapeutic vaccine schedules.

Math Biosci 2021 04 2;334:108556. Epub 2021 Feb 2.

School of Mathematics and Statistics, University of Sydney, Sydney, NSW, Australia. Electronic address:

T cells protect the body from cancer by recognising tumour-associated antigens. Recognising these antigens depends on multiple factors, one of which is T cell avidity, i.e., the total interaction strength between a T cell and a cancer cell. While both high- and low-avidity T cells can kill cancer cells, durable anti-cancer immune responses require the selection of high-avidity T cells. Previous experimentation with anti-cancer vaccines, however, has shown that most vaccines elicit low-avidity T cells. Optimising vaccine schedules may remedy this by preferentially selecting high-avidity T cells. Here, we use mathematical modelling to develop a simple, phenomenological model of avidity selection that may identify vaccine schedules that disproportionately favour low-avidity T cells. We calibrate our model to our prior, more complex model, and then validate it against several experimental data sets. We find that the sensitivity of the model's parameters change with vaccine dosage, which allows us to use a patient's data and clinical history to screen for suitable vaccine strategies.
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http://dx.doi.org/10.1016/j.mbs.2021.108556DOI Listing
April 2021

Connecting the Dots: Translating the Vaginal Microbiome Into a Drug.

J Infect Dis 2021 06;223(12 Suppl 2):S296-S306

Osel, Inc., Mountain View, California, USA.

A Lactobacillus-dominated vaginal microbiota (VMB) has been associated with health and considered an important host defense mechanism against urogenital infections. Conversely, depletion of lactobacilli and increased microbial diversity, amplifies the risk of adverse gynecologic and obstetric outcomes. A common clinical condition that exemplifies dysbiosis is bacterial vaginosis (BV). BV is currently treated with antibiotics, but frequently recurs, due in part to persistent dysbiosis and failure of lactobacilli to repopulate the vagina. New treatment options are needed to address BV. The VMB is relatively simple and optimally dominated by one or several species of Lactobacillus. Lactobacillus crispatus is strongly associated with vaginal health and depleted in dysbiosis. Replenishing the dysbiotic VMB with protective L. crispatus CTV-05 is a promising approach to prevent recurrent infections and improve women's health. Here we discuss confirmation of this approach with the microbiome-based biologic drug, LACTIN-V (L. crispatus CTV-05), focusing on prevention of BV recurrence.
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http://dx.doi.org/10.1093/infdis/jiaa676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8502429PMC
June 2021

Physics approaches to the spatial distribution of immune cells in tumors.

Rep Prog Phys 2021 Feb;84(2):022601

Department of Physics and Astronomy, University of California, Irvine, Irvine, CA 92697, United States of America. Department of Immuno-Oncology, City of Hope Comprehensive Cancer Center and Beckman Research Institute, 1500 East Duarte Road, Duarte, CA 91010, United States of America.

The goal of immunotherapy is to mobilize the immune system to kill cancer cells. Immunotherapy is more effective and, in general, the prognosis is better, when more immune cells infiltrate the tumor. We explore the question of whether the spatial distribution rather than just the density of immune cells in the tumor is important in forecasting whether cancer recurs. After reviewing previous work on this issue, we introduce a novel application of maximum entropy to quantify the spatial distribution of discrete point-like objects. We apply our approach to B and T cells in images of tumor tissue taken from triple negative breast cancer patients. We find that the immune cells are more spatially dispersed in good clinical outcome (no recurrence of cancer within at least 5 years of diagnosis) compared to poor clinical outcome (recurrence within 3 years of diagnosis). Our results highlight the importance of spatial distribution of immune cells within tumors with regard to clinical outcome, and raise new questions on their role in cancer recurrence.
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http://dx.doi.org/10.1088/1361-6633/abcd7bDOI Listing
February 2021

Mature Dendritic Cells May Promote High-Avidity Tuning of Vaccine T Cell Responses.

Front Immunol 2020 30;11:584680. Epub 2020 Oct 30.

School of Mathematics and Statistics, University of Sydney, Sydney, NSW, Australia.

Therapeutic vaccines can elicit tumor-specific cytotoxic T lymphocytes (CTLs), but durable reductions in tumor burden require vaccines that stimulate high-avidity CTLs. Recent advances in immunotherapy responses have led to renewed interest in vaccine approaches, including dendritic cell vaccine strategies. However, dendritic cell requirements for vaccines that generate potent anti-tumor T-cell responses are unclear. Here we use mathematical modeling to show that, counterintuitively, increasing levels of immature dendritic cells may lead to selective expansion of high-avidity CTLs. This finding is in contrast with traditional dendritic cell vaccine approaches that have sought to harness ex vivo generated mature dendritic cells. We show that the injection of vaccine antigens in the context of increased numbers of immature dendritic cells results in a decreased overall peptide:MHC complex load that favors high-avidity CTL activation and expansion. Overall, our results provide a firm basis for further development of this approach, both alone and in combination with other immunotherapies such as checkpoint blockade.
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http://dx.doi.org/10.3389/fimmu.2020.584680DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662095PMC
June 2021

A Phase II Clinical Trial of Pembrolizumab and Enobosarm in Patients with Androgen Receptor-Positive Metastatic Triple-Negative Breast Cancer.

Oncologist 2021 02 24;26(2):99-e217. Epub 2020 Nov 24.

Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center and Beckman Research Institute, Duarte, California, USA.

Lessons Learned: The combination of enobosarm and pembrolizumab was well tolerated and showed a modest clinical benefit rate of 25% at 16 weeks. Future trials investigating androgen receptor-targeted therapy in combination with immune checkpoint inhibitors are warranted.

Background: Luminal androgen receptor is a distinct molecular subtype of triple-negative breast cancer (TNBC) defined by overexpression of androgen receptor (AR). AR-targeted therapy has shown modest activity in AR-positive (AR+) TNBC. Enobosarm (GTx-024) is a nonsteroidal selective androgen receptor modulator (SARM) that demonstrates preclinical and clinical activity in AR+ breast cancer. The current study was designed to explore the safety and efficacy of the combination of enobosarm and pembrolizumab in patients with AR+ metastatic TNBC (mTNBC).

Methods: This study was an open-label phase II study for AR+ (≥10%, 1+ by immunohistochemistry [IHC]) mTNBC. Eligible patients received pembrolizumab 200 mg intravenous (IV) every 3 weeks and enobosarm 18 mg oral daily. The primary objective was to evaluate the safety of enobosarm plus pembrolizumab and determine the response rate. Peripheral blood, tumor biopsies, and stool samples were collected for correlative analysis.

Results: The trial was stopped early because of the withdrawal of GTx-024 drug supply. Eighteen patients were enrolled, and 16 were evaluable for responses. Median age was 64 (range 36-81) years. The combination was well tolerated, with only a few grade 3 adverse events: one dry skin, one diarrhea, and one musculoskeletal ache. The responses were 1 of 16 (6%) complete response (CR), 1 of 16 (6%) partial response (PR), 2 of 16 (13%) stable disease (SD), and 12 of 16 (75%) progressive disease (PD). Response rate (RR) was 2 of 16 (13%). Clinical benefit rate (CBR) at 16 weeks was 4 of 16 (25%). Median follow-up was 24.9 months (95% confidence interval [CI], 17.5-30.9). Progression-free survival (PFS) was 2.6 months (95% CI, 1.9-3.1) and overall survival (OS) was 25.5 months (95% CI, 10.4-not reached [NR]).

Conclusion: The combination of enobosarm and pembrolizumab was well tolerated, with a modest clinical benefit rate of 25% at 16 weeks in heavily pretreated AR+ TNBC without preselected programmed death ligand-1 (PD-L1). Future clinical trials combining AR-targeted therapy with immune checkpoint inhibitor (ICI) for AR+ TNBC warrant investigation.
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http://dx.doi.org/10.1002/onco.13583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873338PMC
February 2021

Purinergic Signaling Within the Tumor Microenvironment.

Adv Exp Med Biol 2021 ;1270:73-87

Department of Immuno-Oncology, City of Hope Comprehensive Cancer Center, Duarte, CA, USA.

Accumulating studies have clearly demonstrated high concentrations of extracellular ATP (eATP) within the tumor microenvironment (TME). Implications of these findings are multifold as ATP-mediated purinergic signaling has been shown to mediate a variety of cancer-related processes, including cell migration, resistance to cytotoxic therapy, and immune regulation. Broad roles of ATP within the tumor microenvironment are linked to the abundance of ATP-regulated purinergic receptors on cancer and stromal and various immune cell types, as well as on the importance of ATP release and signaling in the regulation of multiple cellular processes. ATP release and downstream purinergic signaling are emerging as a central regulator of tumor growth and an important target for therapeutic intervention. In this chapter, we summarize the major roles of purinergic signaling in the tumor microenvironment with a specific focus on its critical roles in the induction of immunogenic cancer cell death and immune modulation.
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http://dx.doi.org/10.1007/978-3-030-47189-7_5DOI Listing
January 2021

Predicting Relapse in Patients With Triple Negative Breast Cancer (TNBC) Using a Deep-Learning Approach.

Front Physiol 2020 23;11:511071. Epub 2020 Sep 23.

Department of Bioengineering, Northeastern University, Boston, MA, United States.

The abundance and/or location of tumor infiltrating lymphocytes (TILs), especially CD8 T cells, in solid tumors can serve as a prognostic indicator in various types of cancer. However, it is often difficult to select an appropriate threshold value in order to stratify patients into well-defined risk groups. It is also important to select appropriate tumor regions to quantify the abundance of TILs. On the other hand, machine-learning approaches can stratify patients in an unbiased and automatic fashion. Based on immunofluorescence (IF) images of CD8 T lymphocytes and cancer cells, we develop a machine-learning approach which can predict the risk of relapse for patients with Triple Negative Breast Cancer (TNBC). Tumor-section images from 9 patients with poor outcome and 15 patients with good outcome were used as a training set. Tumor-section images of 29 patients in an independent cohort were used to test the predictive power of our algorithm. In the test cohort, 6 (out of 29) patients who belong to the poor-outcome group were all correctly identified by our algorithm; for the 23 (out of 29) patients who belong to the good-outcome group, 17 were correctly predicted with some evidence that improvement is possible if other measures, such as the grade of tumors, are factored in. Our approach does not involve arbitrarily defined metrics and can be applied to other types of cancer in which the abundance/location of CD8 T lymphocytes/other types of cells is an indicator of prognosis.
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http://dx.doi.org/10.3389/fphys.2020.511071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538858PMC
September 2020

Association of molecular characteristics with survival in advanced non-small cell lung cancer patients treated with checkpoint inhibitors.

Lung Cancer 2020 08 24;146:174-181. Epub 2020 May 24.

Department of Medical Oncology and Therapeutics Research, City of Hope, Duarte, CA, USA; Division of Medical Oncology, Cedars-Sinai Medical Center, USA. Electronic address:

Objectives: Immune checkpoint inhibitors (ICIs) have changed the landscape of lung cancer therapy. However significant proportions of patients have primary or acquired resistance to ICIs. Molecular characterization is critical for patient selection and overcoming resistance to checkpoint inhibitors. The purpose of this study is to investigate the molecular characteristics associated with ICIs outcomes in advanced non-small cell lung cancer (NSCLC) patients.

Materials And Methods: All advanced stage NSCLC patients at City of Hope who received ICIs (pembrolizumab, nivolumab, atezolizumab, and durvalumab) were identified retrospectively. Overall survival (OS, from the start of the ICIs), Pathology and information on genomic alterations (GAs) including next-generation sequencing (NGS) data, tumor mutation burden (TMB), and Programmed death-ligand 1 (PD-L1) levels were collected. Chi-square and Fisher's exact test, Log-rank test were used for comparison of demographics, and survival curves respectively. Univariate and multivariate COX proportional hazards model was used for survival analysis.

Results: 346 NSCLC patients were identified. Univariate and multivariate analysis found the association of OS with PD-L1 level ≥50% (Hazard ratio [HR], 0.19; 95% confidence interval [CI], 0.06-0.59; P < 0.01), EGFR (HR 7.38; 95% CI, 1.15-47.42; P < 0.05), and TET2 (HR 0.15; 95% CI, 0.03-0.90; P < 0.05). The median OS was not reached [NR] for the 12 patients who had genomic alterations (GAs) in TET2 (12/108, 11%) versus (vs) 11.5 months in TET2 negative patients (98/108, 89%). Interestingly, GAs in TET2 and FANCA were mutually exclusive and patients who had GAs in FANCA gene (6%) had shorter OS (5.5 months vs 14.5 months, Log-rank test, P < 0.05).

Conclusions: We described the clinical and molecular features of NSCLC patients treated with ICIs. The association of GAs in TET2 with longer OS and its mutual exclusivity with FANCA GAs were insightful for developing novel therapeutic strategies to improve ICIs outcomes in NSCLC.
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http://dx.doi.org/10.1016/j.lungcan.2020.05.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8158847PMC
August 2020

Deficiency Leads to Decreased Numbers of Peripheral Blood B Cells and Defective Germinal Center Reactions.

Immunohorizons 2020 05 20;4(5):274-281. Epub 2020 May 20.

Department of Immuno-Oncology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010; and

Rho family GTPases are critical for normal B cell development and function, and their activity is regulated by a large and complex network of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). However, the role of GAPs in B cell development is poorly understood. In this study, we show that the novel Rac-GAP ARHGAP25 is important for B cell development in mice in a CXCR4-dependent manner. We show that deficiency in mice leads to a significant decrease in peripheral blood B cell numbers as well as defects in mature B cell differentiation. B cells respond to Ag stimulation in vitro and in vivo but have impaired germinal center formation and decreased IgG1 class switching. Additionally, B cells show evidence of increased baseline motility and augmented chemotaxis to CXCL12. Taken together, these studies demonstrate an important role for 25 in peripheral B cell development and Ag response.
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http://dx.doi.org/10.4049/immunohorizons.2000021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7301639PMC
May 2020

Systemic Correlates of the Tumor Microenvironment.

Cancer Treat Res 2020 ;180:97-109

Department of Immuno-Oncology, City of Hope Comprehensive Cancer Center, Duarte, CA, USA.

It is increasingly recognized that cancer does not involve only formation of a tumor, but also systemic changes in the host. Alterations in number, spatial relationship, and function of immune cells have been identified in cancer patients' blood, lymph nodes, spleen, and bone marrow. Importantly, these changes correlate with clinical outcome, demonstrating that systemic effects may persist in some patients after initial therapy that underlie future relapse. In this chapter, we will review these recent findings on the systemic effects of cancer.
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http://dx.doi.org/10.1007/978-3-030-38862-1_3DOI Listing
September 2020

Breast cancer induces systemic immune changes on cytokine signaling in peripheral blood monocytes and lymphocytes.

EBioMedicine 2020 Feb 22;52:102631. Epub 2020 Jan 22.

Department of Immuno-Oncology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, 1500 East Duarte Road, Duarte, CA 91010, USA. Electronic address:

Background: It is increasingly recognized that cancer progression induces systemic immune changes in the host. Alterations in number and function of immune cells have been identified in cancer patients' peripheral blood and lymphoid organs. Recently, we found dysregulated cytokine signaling in peripheral blood T cells from breast cancer (BC) patients, even those with localized disease.

Methods: We used phosphoflow cytometry to determine the clinical significance of cytokine signaling responsiveness in peripheral blood monocytes from non-metastatic BC patients at diagnosis. We also examined the correlation between cytokine signaling in peripheral monocytes and the number of tumor-infiltrating macrophages in paired breast tumors.

Findings: Our results show that cytokine (IFNγ) signaling may also be dysregulated in peripheral blood monocytes at diagnosis, specifically in BC patients who later relapsed. Some patients exhibited concurrent cytokine signaling defects in monocytes and lymphocytes at diagnosis, which predict the risk of future relapse in two independent cohorts of BC patients. Moreover, IFNγ signaling negatively correlates with expression of CSF1R on monocytes, thus modulating their ability to infiltrate into tumors.

Interpretation: Our results demonstrate that tumor-induced systemic immune changes are evident in peripheral blood immune cells for both myeloid and lymphoid lineages, and point to cytokine signaling responsiveness as important biomarkers to evaluate the overall immune status of BC patients.

Funding: This study was supported by the Department of Defense Breast Cancer Research Program (BCRP), The V Foundation, Stand Up to Cancer (SU2C), and Breast Cancer Research Foundation (BCRF).
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http://dx.doi.org/10.1016/j.ebiom.2020.102631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6992943PMC
February 2020

A Pilot Feasibility Study of Yttrium-90 Liver Radioembolization Followed by Durvalumab and Tremelimumab in Patients with Microsatellite Stable Colorectal Cancer Liver Metastases.

Oncologist 2020 05 19;25(5):382-e776. Epub 2019 Dec 19.

Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, California, USA.

Lessons Learned: Radioembolization with yttrium-90 resin microspheres can be combined safely with full doses of durvalumab and tremelimumab in patients with metastatic colorectal cancer. Regional radioembolization with yttrium-90 resin microspheres did not result in any hepatic or extrahepatic responses to a combination of durvalumab and tremelimumab. The lack of immunomodulatory responses to yttrium-90 on biopsies before and after treatment rules out a potential role for this strategy in converting a "cold tumor" into an "inflamed," immune responsive tumor.

Background: PD-1 inhibitors have been ineffective in microsatellite stable (MSS) metastatic colorectal cancer (CRC). Preclinical models suggest that radiation therapy may sensitize MSS CRC to PD-1 blockade.

Methods: Patients with MSS metastatic CRC with liver-predominant disease who progressed following at least one prior line of treatment were treated with yttrium-90 (Y90) radioembolization to the liver (SIR-Spheres; Sirtex, Woburn, MA) followed 2-3 weeks later by the combination of durvalumab and tremelimumab. A Simon two-stage design was implemented, with a planned expansion to 18 patients if at least one response was noted in the first nine patients.

Results: Nine patients enrolled in the first stage of the study, all with progressive disease (PD) during or after their first two cycles of treatment. Per preplanned design, the study was closed because of futility. No treatment-related grade 3 or greater toxicities were recorded. Correlative studies with tumor biopsies showed low levels of tumor-infiltrating lymphocyte (TIL) infiltration in tumor cancer islands before and after Y90 radioembolization.

Conclusion: Y90 radioembolization can be added safely to durvalumab and tremelimumab but did not promote tumor-directed immune responses against liver-metastasized MSS CRC.
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http://dx.doi.org/10.1634/theoncologist.2019-0924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7216435PMC
May 2020

STAT3 Activation-Induced Fatty Acid Oxidation in CD8 T Effector Cells Is Critical for Obesity-Promoted Breast Tumor Growth.

Cell Metab 2020 01 21;31(1):148-161.e5. Epub 2019 Nov 21.

Department of Immuno-Oncology, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA. Electronic address:

Although obesity is known to be critical for cancer development, how obesity negatively impacts antitumor immune responses remains largely unknown. Here, we show that increased fatty acid oxidation (FAO) driven by activated STAT3 in CD8 T effector cells is critical for obesity-associated breast tumor progression. Ablating T cell Stat3 or treatment with an FAO inhibitor in obese mice spontaneously developing breast tumor reduces FAO, increases glycolysis and CD8 T effector cell functions, leading to inhibition of breast tumor development. Moreover, PD-1 ligation in CD8 T cells activates STAT3 to increase FAO, inhibiting CD8 T effector cell glycolysis and functions. Finally, leptin enriched in mammary adipocytes and fat tissues downregulates CD8 T cell effector functions through activating STAT3-FAO and inhibiting glycolysis. We identify a critical role of increased oxidation of fatty acids driven by leptin and PD-1 through STAT3 in inhibiting CD8 T effector cell glycolysis and in promoting obesity-associated breast tumorigenesis.
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http://dx.doi.org/10.1016/j.cmet.2019.10.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6949402PMC
January 2020

Optimisation of anti-cancer peptide vaccines to preferentially elicit high-avidity T cells.

J Theor Biol 2020 02 6;486:110067. Epub 2019 Nov 6.

Department of Immuno-Oncology, City of Hope and Beckman Research Institute, Duarte, CA, USA. Electronic address:

Therapeutic cancer vaccines often do not substantially reduce tumour burden, despite stimulating anti-tumour cytotoxic T lymphocytes (CTLs). Recent experiments have shown that the majority of vaccine-elicited CTLs may be of low-avidity. Moreover, low-avidity CTLs, which are abundant, do not kill cancer cells and potentially inhibit the ability of high-avidity T cells to kill cancer cells. By modelling CTL selection using a system of ordinary differential equations, we show that the efficacy of the peptide vaccine may be improved by controlling its delivery and dosage to preferentially elicit high-avidity CTLs. Our simulations predict that weekly, reduced doses of a vaccine may result in a greater than 90% reduction in cancer concentration. By contrast, a standard vaccine protocol such as a high-dose injection given every 2 weeks induces only a 65% reduction. Our model demonstrates a proof-of-concept approach to targeting immune responses for CTL selection, thereby offering a technique to potentially improve existing therapies.
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http://dx.doi.org/10.1016/j.jtbi.2019.110067DOI Listing
February 2020

Phenotypic Switching of Naïve T Cells to Immune-Suppressive Treg-Like Cells by Mutant KRAS.

J Clin Med 2019 Oct 18;8(10). Epub 2019 Oct 18.

Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA 91010, USA.

Oncogenic (mutant) Ras protein Kirsten rat sarcoma viral oncogene homolog (KRAS) promotes uncontrolled proliferation, altered metabolism, and loss of genome integrity in a cell-intrinsic manner. Here, we demonstrate that CD4 T cells when incubated with tumor-derived exosomes from mutant (MT) KRAS non-small-cell lung cancer (NSCLC) cells, patient sera, or a mouse xenograft model, induce phenotypic conversion to FOXP3 Treg-like cells that are immune-suppressive. Furthermore, transfecting T cells with MT KRAS cDNA alone induced phenotypic switching and mathematical modeling supported this conclusion. Single-cell sequencing identified the interferon pathway as the mechanism underlying the phenotypic switch. These observations highlight a novel cytokine-independent, cell-extrinsic role for KRAS in T cell phenotypic switching. Thus, targeting this new class of Tregs represents a unique therapeutic approach for NSCLC. Since KRAS is the most frequently mutated oncogene in a wide variety of cancers, the findings of this investigation are likely to be of broad interest and have a large scientific impact.
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http://dx.doi.org/10.3390/jcm8101726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6832522PMC
October 2019

Immune overdrive signature in colorectal tumor subset predicts poor clinical outcome.

J Clin Invest 2019 10;129(10):4464-4476

Department of Immuno-Oncology, and.

The prognostic value of immune cell infiltration within the tumor microenvironment (TME) has been extensively investigated via histological and genomic approaches. Based on the positive prognostic value of T cell infiltration, Immunoscore has been developed and validated for predicting risk of recurrence for colorectal cancer (CRC). Also, association between a consensus T helper 1 (Th-1) immune response and favorable clinical outcomes has been observed across multiple cancer types. Here, we reanalyzed public genomic data sets from The Cancer Genome Atlas (TCGA) and NCBI Gene Expression Omnibus (NCBI-GEO) and performed multispectral immunohistochemistry (IHC) on a cohort of colorectal tumors. We identified and characterized a risk group, representing approximately 10% of CRC patients, with high intratumoral CD8+ T cell infiltration, but poor prognosis. These tumors included both microsatellite instable (MSI) and stable (MSS) phenotypes and had a high density of tumor-associated macrophages (TAMs) that expressed CD274 (programmed death-ligand 1 [PD-L1]), TGF-β activation, and an immune overdrive signature characterized by the overexpression of immune response and checkpoint genes. Our findings illustrate that CRC patients may have poor prognosis despite high CD8+ T cell infiltration and provide CD274 as a simple biomarker for identifying these patients.
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http://dx.doi.org/10.1172/JCI127046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6763253PMC
October 2019

Resident memory CD8+ T cells within cancer islands mediate survival in breast cancer patients.

JCI Insight 2019 10 3;4(19). Epub 2019 Oct 3.

Department of Immuno-Oncology.

CD8+ tumor-infiltrating lymphocytes (TILs) correlate with relapse-free survival (RFS) in most cancer types, including breast cancer. However, subset composition, functional status, and spatial location of CD8+ TILs in relation to RFS in human breast tumors remain unclear. Spatial tissue analysis via quantitative immunofluorescence showed that infiltration of CD8+ T cells into cancer islands was more significantly associated with RFS than CD8+ T cell infiltration into either tumor stroma or total tumor. Localization into cancer islands within tumors is mediated by expression of the integrin CD103, which is a marker for tissue-resident memory T cells (TRMs). Analysis of fresh tumor samples revealed that CD8+ TRMs are functionally similar to other CD8+ TILs, suggesting that the basis of their protective effect is their spatial distribution rather than functional differences. Indeed, CD103+ TRMs, as compared with CD103-CD8+ TILs, are enriched within cancer islands, and CD8+ TRM proximity to cancer cells drives the association of CD8+ TIL densities with RFS. Together, these findings reveal the importance of cancer island-localized CD8+ TRMs in surveillance of the breast tumor microenvironment and as a critical determinant of RFS in patients with breast cancer.
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http://dx.doi.org/10.1172/jci.insight.130000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6795408PMC
October 2019

Connecting blood and intratumoral T cell activity in predicting future relapse in breast cancer.

Nat Immunol 2019 09 8;20(9):1220-1230. Epub 2019 Jul 8.

Department of Immuno-Oncology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA, USA.

Regulatory T (T) cells play a major role in the development of an immunosuppressive tumor microenvironment. The origin of intratumoral T cells and their relationship with peripheral blood T cells remain unclear. T cells consist of at least three functionally distinct subpopulations. Here we show that peripheral blood CD45RAFOXP3 T cells (T II cells) are phenotypically closest to intratumoral T cells, including in their expression of CCR8. Analyses of T cell antigen receptor repertoires further support the hypothesis that intratumoral T cells may originate primarily from peripheral blood T II cells. Moreover, the signaling responsiveness of peripheral blood T II cells to immunosuppressive, T helper type 1 (T1) and T helper type 2 (T2) cytokines reflects intratumoral immunosuppressive potential, and predicts future relapse in two independent cohorts of patients with breast cancer. Together, our findings give important insights into the relationship between peripheral blood T cells and intratumoral T cells, and highlight cytokine signaling responsiveness as a key determinant of intratumoral immunosuppressive potential and clinical outcome.
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http://dx.doi.org/10.1038/s41590-019-0429-7DOI Listing
September 2019

Synchronous recurrence of concurrent colon adenocarcinoma and dedifferentiated liposarcoma.

BMJ Case Rep 2019 May 13;12(5). Epub 2019 May 13.

Department of Surgery, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA.

A 62-year-old man presented with concurrent sigmoid colon adenocarcinoma and small bowel mesenteric dedifferentiated liposarcoma. Following surgical resection of the colon cancer, complete excision of the mesenteric sarcoma and adjuvant folinic acid, fluorouracil and oxaliplatin (FOLFOX) chemotherapy, the patient demonstrated no radiological evidence of disease for more than 2 years. The patient then developed synchronous recurrence of both cancers: the colon cancer metastasised to the liver and a pelvic lymph node, and the liposarcoma recurred in the original location. The patient underwent additional chemotherapy with complete response of the metastatic colon cancer and stable disease for the liposarcoma. The recurrent mesenteric tumour was subsequently resected. Although concurrent cancers have been reported, this unique case of synchronous recurrence raises interesting hypotheses regarding host-tumour interaction and immune surveillance.
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http://dx.doi.org/10.1136/bcr-2018-228868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6536183PMC
May 2019

Human breast tumor-infiltrating CD8 T cells retain polyfunctionality despite PD-1 expression.

Nat Commun 2018 10 16;9(1):4297. Epub 2018 Oct 16.

Department of Immuno-Oncology, Beckman Research Institute of City of Hope, Duarte, CA, 91010, USA.

Functional CD8 T cells in human tumors play a clear role in clinical prognosis and response to immunotherapeutic interventions. PD-1 expression in T cells involved in chronic infections and tumors such as melanoma often correlates with a state of T-cell exhaustion. Here we interrogate CD8 tumor-infiltrating lymphocytes (TILs) from human breast and melanoma tumors to explore their functional state. Despite expression of exhaustion hallmarks, such as PD-1 expression, human breast tumor CD8 TILs retain robust capacity for production of effector cytokines and degranulation capacity. In contrast, melanoma CD8 TILs display dramatic reduction of cytokine production and degranulation capacity. We show that CD8 TILs from human breast tumors can potently kill cancer cells via bi-specific antibodies. Our data demonstrate that CD8 TILs in human breast tumors retain polyfunctionality, despite PD-1 expression, and suggest that they may be harnessed for effective immunotherapies.
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http://dx.doi.org/10.1038/s41467-018-06653-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6191461PMC
October 2018

Lymph Node Cellular Dynamics in Cancer and HIV: What Can We Learn for the Follicular CD4 (Tfh) Cells?

Front Immunol 2018 27;9:2233. Epub 2018 Sep 27.

Tissue Analysis Core, Immunology Laboratory, Vaccine Research Center, NIAID, NIH, Bethesda, MD, United States.

Lymph nodes (LNs) are central in the generation of adaptive immune responses. Follicular helper CD4 T (Tfh) cells, a highly differentiated CD4 population, provide critical help for the development of antigen-specific B cell responses within the germinal center. Throughout the past decade, numerous studies have revealed the important role of Tfh cells in Human Immunodeficiency Virus (HIV) pathogenesis as well as in the development of neutralizing antibodies post-infection and post-vaccination. It has also been established that tumors influence various immune cell subsets not only in their proximity, but also in draining lymph nodes. The role of local or tumor associated lymph node Tfh cells in disease progression is emerging. Comparative studies of Tfh cells in chronic infections and cancer could therefore provide novel information with regards to their differentiation plasticity and to the mechanisms regulating their development.
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http://dx.doi.org/10.3389/fimmu.2018.02233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6170630PMC
October 2019

Sentinel lymph node B cells can predict disease-free survival in breast cancer patients.

NPJ Breast Cancer 2018 23;4:28. Epub 2018 Aug 23.

1Department of Immuno-Oncology, City of Hope and Beckman Research Institute, Duarte, CA USA.

Tumor invasion into draining lymph nodes, especially sentinel lymph nodes (SLNs), is a key determinant of prognosis and treatment in breast cancer as part of the TNM staging system. Using multicolor histology and quantitative image analysis, we quantified immune cells within SLNs from a discovery cohort of 76 breast cancer patients. We found statistically more in situ CD3 T cells in tumor negative vs. tumor positive nodes (mean of 8878 vs. 6704, respectively,  = 0.006), but no statistical difference in CD20 B cells or CD1a dendritic cells. In univariate analysis, a reduced hazard was seen with a unit increase in log CD3 with HR 0.49 (95% CI 0.30-0.80) and log CD20 with HR 0.37 (95% CI 0.22-0.62). In multivariate analysis, log CD20 remained significant with HR 0.42 (95% CI 0.25-0.69). When restricted to SLN tumor negative patients, increased log CD20 was still associated with improved DFS (HR = 0.26, 95% CI 0.08-0.90). The CD20 results were validated in a separate cohort of 21 patients ( = 11 good outcome,  = 10 poor outcome) with SLN negative triple-negative breast cancer (TNBC) ("good" mean of 7011 vs. "poor" mean of 4656,  = 0.002). Our study demonstrates that analysis of immune cells within SLNs, regardless of tumor invasion status, may provide additional prognostic information, and highlights B cells within SLNs as important in preventing future recurrence.
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http://dx.doi.org/10.1038/s41523-018-0081-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6107630PMC
August 2018

Immune profiling of microsatellite instability-high and polymerase ε ()-mutated metastatic colorectal tumors identifies predictors of response to anti-PD-1 therapy.

J Gastrointest Oncol 2018 Jun;9(3):404-415

Department of Medical Oncology, City of Hope National Medical Center, Duarte, CA, USA.

Background: Microsatellite instability-high (MSI-H) and polymerase ε ()-mutated metastatic colorectal cancer (mCRC) represent hypermutated and ultramutated tumor phenotypes, respectively, that may predict benefit to checkpoint blockade [anti-programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1)].

Methods: Immune profiling through multispectral fluorescent immunohistochemistry (IHC) using a multi-marker staining panel was performed on pretreatment tumor specimens from a cohort of MSI-H or -mutated mCRC patients treated with PD-1 blockade at our institution to identify candidate predictors of response to checkpoint inhibitors.

Results: From 4/2013 to 1/2017, a total of 237 mCRC patients with molecularly profiled tumors were screened. Five MSI-H and three -mutated mCRC patients were treated with checkpoint inhibitors. Immune profiling identified higher CD8+ tumor-infiltrating lymphocytes (TILs) within the tumor microenvironment (TME) of responders (CR or PR as best response) than nonresponders (SD or PD as best response). Responders had significantly higher densities of CD8+ PD-1+ TILs than nonresponders (P=0.0007). PD-L1 expression (P=0.73), CD4+ T-cell density (P=0.39), and CD4+ FOXP3+ T-cell density (P=0.68) did not significantly differ, but the percentage of CD4+ Tbet+ T-cells (Th1 phenotype) was also significantly higher in responders than nonresponders (P=0.0007).

Conclusions: Higher densities of CD8+ TILs, PD-1-expressing CD8+ TILs, and tumor-infiltrating immune cells with a Th1 phenotype in the TME may predict response to checkpoint inhibitors in MSI-H and -mutated mCRC.
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http://dx.doi.org/10.21037/jgo.2018.01.09DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6006042PMC
June 2018

MHC class I loaded ligands from breast cancer cell lines: A potential HLA-I-typed antigen collection.

J Proteomics 2018 03 10;176:13-23. Epub 2018 Jan 10.

Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, United States.

To build a catalog of peptides presented by breast cancer cells, we undertook systematic MHC class I immunoprecipitation followed by elution of MHC class I-loaded peptides in breast cancer cells. We determined the sequence of 3196 MHC class I ligands representing 1921 proteins from a panel of 20 breast cancer cell lines. After removing duplicate peptides, i.e., the same peptide eluted from more than one cell line, the total number of unique peptides was 2740. Of the unique peptides eluted, more than 1750 had been previously identified, and of these, sixteen have been shown to be immunogenic. Importantly, half of these immunogenic peptides were shared between different breast cancer cell lines. MHC class I binding probability was used to plot the distribution of the eluted peptides in accordance with the binding score for each breast cancer cell line. We also determined that the tested breast cancer cells presented 89 mutation-containing peptides and peptides derived from aberrantly translated genes, 7 of which were shared between four or two different cell lines. Overall, the high throughput identification of MHC class I-loaded peptides is an effective strategy for systematic characterization of cancer peptides, and could be employed for design of multi-peptide anticancer vaccines.

Significance: By employing proteomic analyses of eluted peptides from breast cancer cells, the current study has built an initial HLA-I-typed antigen collection for breast cancer research. It was also determined that immunogenic epitopes can be identified using established cell lines and that shared immunogenic peptides can be found in different cancer types such as breast cancer and leukemia. Importantly, out of 3196 eluted peptides that included duplicate peptides in different cells 89 peptides either contained mutation in their sequence or were derived from aberrant translation suggesting that mutation-containing epitopes are on the order of 2-3% in breast cancer cells. Finally, our results suggest that interfering with MHC class I function is one of the mechanisms of how tumor cells escape immune system attack.
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http://dx.doi.org/10.1016/j.jprot.2018.01.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5999401PMC
March 2018
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