Journal Articles

Cancer Immunobiology

Basic research studies that extend knowledge in the field of cancer immunotherapy

Inhibition of TAMs improves the response to docetaxel in castration-resistant prostate cancer

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For men with castration-resistant prostate cancer (CRPC), androgen-deprivation therapy (ADT) often becomes ineffective requiring the addition of docetaxel, a proven effective chemotherapy option. Tumor-associated macrophages (TAMs) are known to provide protumorigenic influences that contribute to treatment failure. In this study, we examined the contribution of TAMs to docetaxel treatment. An increased infiltration of macrophages in CRPC tumors was observed after treatment with docetaxel. Prostate cancer cells treated with docetaxel released more macrophage colony-stimulating factor (M-CSF-1 or CSF-1), IL-10 and other factors, which can recruit and modulate circulating monocytes to promote their protumorigenic functions. Inhibition of CSF-1 receptor kinase signaling with a small molecule antagonist (PLX3397) in CRPC models significantly reduces the infiltration of TAMs and their influences. As such, the addition of PLX3397 to docetaxel treatment resulted in a more durable tumor growth suppression than docetaxel alone. This study reveals a rational strategy to abrogate the influences of TAMs and extend the treatment response to docetaxel in CRPC.

Author Info: (1) Department of Urology and Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. (2) Department of Urology

Author Info: (1) Department of Urology and Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. (2) Department of Urology and Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Department of Paediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA. (3) Department of Urology, Institute of Urology, West China Hospital of Sichuan University, Chengdu, China. (4) Department of Urology, Institute of Urology, West China Hospital of Sichuan University, Chengdu, China. (5) Department of Urology, Institute of Urology, West China Hospital of Sichuan University, Chengdu, China. (6) Plexxikon Inc., Berkeley, California, USA. (7) Plexxikon Inc., Berkeley, California, USA. (8) Department of Urology and Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. (9) Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA. Department of Urology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA. Department of Pediatrics, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA. Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA. Molecular Biology Institute, University of California at Los Angeles, Los Angeles, California, USA.

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Antifibrotic therapy disrupts stromal barriers and modulates the immune landscape in pancreatic ductal adenocarcinoma

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Pancreatic ductal adenocarcinoma (PDA) remains one of the deadliest forms of cancer, in part, because it is largely refractory to current therapies. The failure of most standard therapies in PDA, as well as promising immune therapies, may be largely ascribed to highly unique and protective stromal microenvironments that present significant biophysical barriers to effective drug delivery, that are immunosuppressive, and that can limit the distribution and function of anti-tumor immune cells. Here, we utilized stromal re-engineering to disrupt these barriers and move the stroma toward normalization using a potent antifibrotic agent, halofuginone. In an autochthonous genetically engineered mouse model of PDA, halofuginone disrupted physical barriers to effective drug distribution by decreasing fibroblast activation and reducing key extracellular matrix elements that drive stromal resistance. Concomitantly, halofuginone treatment altered the immune landscape in PDA, with greater immune infiltrate into regions of low hylauronan, which resulted in increased number and distribution of both classically activated inflammatory macrophages and cytotoxic T cells. In concert with a direct effect on carcinoma cells, this led to widespread intratumoral necrosis and reduced tumor volume. These data point to the multifunctional and critical role of the stroma in tumor protection and survival and demonstrate how compromising tumor integrity to move toward a more normal physiologic state through stroma-targeting therapy will likely be an instrumental component in treating PDA.

Author Info: (1) Biomedical Engineering, University of Minnesota. (2) Department of Biomedical Engineering, University of Minnesota. (3) Biomedical Engineering, University of Minnesota. (4) Department of Biomedical Engineering

Author Info: (1) Biomedical Engineering, University of Minnesota. (2) Department of Biomedical Engineering, University of Minnesota. (3) Biomedical Engineering, University of Minnesota. (4) Department of Biomedical Engineering, University of Minnesota pprovenz@umn.edu.

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M2 macrophage-derived exosomes promote cell migration and invasion in colon cancer

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Clinical and experimental evidence has shown that tumor-associated macrophages promote cancer initiation and progression. However, the macrophage-derived molecular determinants that regulate colorectal cancer (CRC) metastasis have not been fully characterized. Here we demonstrate that M2 macrophage-regulated CRC cells migration and invasion is dependent upon M2 macrophage-derived exosomes (MDE). MDE displayed a high expression level of miR-21-5p and miR-155-5p, and MDE-mediated CRC cells migration and invasion depended on these two miRNAs. Mechanistically, miR-21-5p and miR-155-5p were transferred to CRC cells by MDE and bound to the BRG1 coding sequence, downregulating expression of BRG1, which has been identified as a key factor promoting CRC metastasis, yet is downregulated in metastatic CRC cells. Collectively, these findings show that M2 macrophages induce CRC cells migration and invasion and provide significant plasticity of BRG1 expression in response to tumor microenvironments during malignant progression. This dynamic and reciprocal cross-talk between CRC cells and M2 macrophages provides a new opportunity for the treatment of metastatic CRC.

Author Info: (1) Cancer research institute, Tongji Hospital, Tongji Medical College. (2) Department of Oncology, Tongji Hospital, Tongji Medical College. (3) Cancer research institute, Tongji Hospital, Tongji

Author Info: (1) Cancer research institute, Tongji Hospital, Tongji Medical College. (2) Department of Oncology, Tongji Hospital, Tongji Medical College. (3) Cancer research institute, Tongji Hospital, Tongji Medical College. (4) Cancer research institute, Tongji Hospital, Tongji Medical College. (5) Cancer Research Institute, Huazhong University of Science and Technology. (6) Cancer research institute, Tongji Hospital, Tongji Medical College. (7) Cancer Research Institute, Huazhong University of Science and Technology. (8) Cancer research institute, Tongji Hospital, Tongji Medical College. (9) Cancer Research Institute, Huazhong University of Science and Technology. (10) Huazhong University of Science and Technology, Tongji Hospital, Tongji Medical College. (11) Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology. (12) Cancer Research Institute, Tongji Hospital, Tongji Medical College. (13) Cancer research institute, Tongji Hospital, Tongji Medical College ghwang@tjh.tjmu.edu.cn.

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Collapse of the Plasmacytoid Dendritic Cells compartment in advanced cutaneous melanomas by components of the tumor cell secretome

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Melanoma is an immunogenic neoplasm infiltrated by T cells, although these adaptive T cells usually fail to eradicate the tumor. Plasmacytoid dendritic cells (PDCs) are potent regulators of the adaptive immune response and can eliminate melanoma cells via TLR-mediated effector functions. The PDC compartment is maintained by progressively restricted bone marrow progenitors. Terminally differentiated PDCs exit the bone marrow into the circulation, then home to lymph nodes and inflamed peripheral tissues. Infiltration by PDCs is documented in various cancers. However, their role within the melanoma immune contexture is not completely known. We found that in loco-regional primary cutaneous melanoma (PCM), PDC infiltration was heterogeneous, occurred early, and was recurrently localized at the invasive margin, the site where PDCs interact with CD8+ T cells. A reduced PDC density was coupled with an increased Breslow thickness and somatic mutations at the NRAS p.Q61 codon. Compared to what was seen in PCM, high numbers of PDCs were found in regional lymph nodes, as also identified by in silico analysis. In contrast, in metastatic melanoma (MM) patients, PDCs were mostly absent in the tumor tissues and were significantly reduced in the circulation, particularly in the advanced M1c group. Exposure of circulating PDCs to melanoma cell supernatant (SN-mel) depleted of extracellular vesicles resulted in significant PDC death. SN-mel exposure also resulted in a defect of PDC differentiation from CD34+ progenitors. These findings indicate that soluble components released by melanoma cells support the collapse of the PDC compartment, with clinical implications for refining TLR-agonist based trials.

Author Info: (1) Department of Molecular and Translational Medicine, University of Brescia. (2) Department of Molecular and Translational Medicine, University of Brescia. (3) ASST SPEDALI CIVILI DI

Author Info: (1) Department of Molecular and Translational Medicine, University of Brescia. (2) Department of Molecular and Translational Medicine, University of Brescia. (3) ASST SPEDALI CIVILI DI BRESCIA. (4) Department of Molecular and Translational Medicine, University of Brescia. (5) Medical Oncology, ASST SPEDALI CIVILI DI BRESCIA. (6) DMMT, University of Brescia. (7) Department of Molecular and Translational Medicine, University of Brescia. (8) Department of Molecular and Translational Medicine, Unit of Biostatistics, University of Brescia. (9) Pathology Division, Esine Hospital, ASL Vallecamonica Sebino. (10) Pathology, Azienda USL della Romagna. (11) Department of Molecular and Translational Medicine, University of Brescia. (12) Division of Medical Oncology and Immunotherapy, Department of Oncology, University Hospital of Siena, Istituto Toscano Tumori. (13) Division of Medical Oncology and Immunotherapy, Department of Oncology, University Hospital of Siena, Istituto Toscano Tumori. (14) ASST SPEDALI CIVILI DI BRESCIA. (15) Dep.Diagnostic and Public Health, University and Hospital Trust of Verona. (16) Transfusion Medicine, ASST SPEDALI CIVILI DI BRESCIA. (17) ASST SPEDALI CIVILI DI BRESCIA. (18) Applied Research on Cancer Centre (ARC-Net) and Department of Diagnostics and Public Health-Section of Pathology, University and Hospital Trust of Verona. (19) Department of Molecular and Translational Medicine, University of Brescia. (20) ASST SPEDALI CIVILI DI BRESCIA. (21) Pathology Unit, Department of Molecular and Translational Medicine, University of Brescia. (22) Department of Molecular and Translational Medicine, University of Brescia william.vermi@unibs.it.

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Calnexin impairs the antitumor immunity of CD4+ and CD8+ T cells

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Elucidation of the mechanisms of T cell-mediated antitumor responses will provide information for the rational design and development of cancer immunotherapies. Here, we found that calnexin, an endoplasmic reticulum (ER) chaperone protein, is significantly upregulated in oral squamous cell carcinoma (OSCC). Upregulation of its membranous expression on OSCC cells is associated with inhibited T-cell infiltration in tumor tissues and correlates with poor survival of OSCC patients. We found that calnexin inhibits the proliferation of CD4+ and CD8+ T cells isolated from the whole blood of healthy donors and OSCC patients and inhibits the secretion of IFNgamma, TNFalpha, and IL2 from these cells. Furthermore, in a melanoma model, knockdown of calnexin enhanced the infiltration and effector functions of T cells in the tumor microenvironment and conferred better control of tumor growth, whereas treatment with a recombinant calnexin protein impaired the infiltration and effector functions of T cells and promoted tumor growth. We also found that calnexin enhanced the expression of PD-1 on CD4+ and CD8+ T cells by restraining the DNA methylation status of a CpG island in the PD-1 promoter. Thus, this work uncovers a mechanism by which T-cell antitumor responses are regulated by calnexin in tumor cells and suggests that calnexin might serve as a potential target for the improvement of antitumor immunotherapy.

Author Info: (1) Hospital of Stomatology,Sun yat-sen University. (2) Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Stomatological Hospital, Sun Yat-Sen University. (3) Hospital of

Author Info: (1) Hospital of Stomatology,Sun yat-sen University. (2) Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Stomatological Hospital, Sun Yat-Sen University. (3) Hospital of Stomatology,Sun yat-sen University. (4) Hospital of Stomatology,Sun yat-sen University. (5) Hospital of Stomatology,Sun yat-sen University. (6) Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Stomatological Hospital, Sun Yat-Sen University. (7) Hospital of Stomatology,Sun yat-sen University. (8) Hospital of Stomatology,Sun yat-sen University. (9) Hospital of Stomatology,Sun yat-sen University. (10) Hospital of Stomatology,Sun yat-sen University. (11) Hospital of Stomatology,Sun yat-sen University. (12) Zhongshan School of Medicine, Sun Yat-sen University. (13) Guanghua School of Stomatology, Sun Yat-sen University. (14) College of Life Sciences, Sun Yat-sen University. (15) Zhongshan School of Medicine, Sun Yat-sen University. (16) Immunobiology, Yale University School of Medicine. (17) Guanghua School of Stomatology, Sun Yat-sen University. (18) Guangdong Provincial Key Laboratory of Stomatology, Stomatological Hospital, Sun Yat-Sen University, Guanghua School of Stomatology, Stomatological Hospital, Guangdong Provincial Key Laboratory of Stomatology, SunYat-sen University wangzh75@mail.sysu.edu.cn.

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Epigenetic regulators of programmed death-ligand 1 expression in human cancers

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The programmed cell death protein 1-programmed death-ligand 1 (PD-L1) axis has been successfully targeted in clinics and the use of immune check-point inhibitors have shown durable antitumor response in untreated or heavily treated advanced stage cancer. PD-L1 upregulation has been found to correlate with poor prognosis in multiple cancer types and expression of PD-L1 in intratumoral compartment has been suggested to influence immune response and act as a key determinant of checkpoint immunotherapy efficacy. Hence it becomes critical to understand the regulation of PD-L1 expression in cancer. Role of oncogenic signaling pathways and transcription factors such as PI3K-AKT, MEK-ERK, JAK-STAT, MYC, HIF-1alpha, AP-1 and NF-kappaB is well established in inducing PD-L1 expression. Even the structural variations resulting in the truncation of the 3' untranslated region (UTR) of PD-L1 has been shown to upregulate PD-L1 expression in multiple cancer types. Since microRNAs carry out post-transcriptional gene silencing by binding to the 3' UTR of its target messenger RNA, truncation of PD-L1 3' UTR can result in alleviation of PD-L1 suppression mediated by microRNA, leading to its overexpression. Other epigenetic modifications, such as promoter DNA methylation and histone modifications can also play crucial role in regulating PD-L1 expression. Here, we review recent findings and evidence on epigenetic mechanisms that regulate PD-L1 expression and the biological and clinical implications of such regulation in cancer.

Author Info: (1) Dept. of Medical Oncology, Dr. B R Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India

Author Info: (1) Dept. of Medical Oncology, Dr. B R Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India. Electronic address: sksingla@gmail.com. (2) Dept. of Medical Oncology, Dr. B R Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India.

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Extracellular RNA Sensing by Pattern Recognition Receptors

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RNA works as a genome and messenger in RNA viruses, and it sends messages in most of the creatures of the Earth, including viruses, bacteria, fungi, plants, and animals. The human innate immune system has evolved to detect single- and double-stranded RNA molecules from microbes by pattern recognition receptors and induce defense reactions against infections such as the production of type I interferons and inflammatory cytokines. To avoid cytokine toxicity causing chronic inflammation or autoimmunity by sensing self-RNA, the activation of RNA sensors is strictly regulated. All of the Toll-like receptors that recognize RNA are localized to endosomes/lysosomes, which require internalization of RNA for sensing through an endocytic pathway. RIG-I-like receptors sense RNA in cytosol. These receptors are expressed in a cell type-specific fashion, enabling sensing of RNA for a wide range of microbial invasions. At the same time, both endosomal and cytoplasmic receptors have strategies to respond only to RNA of pathogenic microorganisms or dying cells. RNA are potential vaccine adjuvants for immune enhancement against cancer and provide a benefit for vaccinations. Understanding the detailed molecular mechanisms of the RNA-sensing system will help us to broaden the clinical utility of RNA adjuvants for patients with incurable diseases.

Author Info: (1) Department of Vaccine Immunology, Hokkaido University Graduate School of Medicine, Sapporo, JapanMegumi.Tatematsu@med.uni-muenchen.de. Dr. von Hauner Children's Hospital, Department of Pediatrics, University Hospital, LMU Munich

Author Info: (1) Department of Vaccine Immunology, Hokkaido University Graduate School of Medicine, Sapporo, JapanMegumi.Tatematsu@med.uni-muenchen.de. Dr. von Hauner Children's Hospital, Department of Pediatrics, University Hospital, LMU Munich, Munich, GermanyMegumi.Tatematsu@med.uni-muenchen.de. (2) Department of Vaccine Immunology, Hokkaido University Graduate School of Medicine, Sapporo, Japan. (3) Department of Vaccine Immunology, Hokkaido University Graduate School of Medicine, Sapporo, Japan. (4) Department of Vaccine Immunology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.

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Analysis of Single-Cell RNA-Seq Identifies Cell-Cell Communication Associated with Tumor Characteristics

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Tumor ecosystems are composed of multiple cell types that communicate by ligand-receptor interactions. Targeting ligand-receptor interactions (for instance, with immune checkpoint inhibitors) can provide significant benefits for patients. However, our knowledge of which interactions occur in a tumor and how these interactions affect outcome is still limited. We present an approach to characterize communication by ligand-receptor interactions across all cell types in a microenvironment using single-cell RNA sequencing. We apply this approach to identify and compare the ligand-receptor interactions present in six syngeneic mouse tumor models. To identify interactions potentially associated with outcome, we regress interactions against phenotypic measurements of tumor growth rate. In addition, we quantify ligand-receptor interactions between T cell subsets and their relation to immune infiltration using a publicly available human melanoma dataset. Overall, this approach provides a tool for studying cell-cell interactions, their variability across tumors, and their relationship to outcome.

Author Info: (1) Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge MA, 02139, USA. (2) Discovery, Merrimack Pharmaceuticals, Inc., Cambridge MA, 02139, USA. (3) Department of

Author Info: (1) Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge MA, 02139, USA. (2) Discovery, Merrimack Pharmaceuticals, Inc., Cambridge MA, 02139, USA. (3) Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge MA, 02139, USA. (4) Discovery, Merrimack Pharmaceuticals, Inc., Cambridge MA, 02139, USA. (5) Discovery, Merrimack Pharmaceuticals, Inc., Cambridge MA, 02139, USA. (6) Discovery, Merrimack Pharmaceuticals, Inc., Cambridge MA, 02139, USA. (7) Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge MA, 02139, USA. (8) Discovery, Merrimack Pharmaceuticals, Inc., Cambridge MA, 02139, USA. Electronic address: araue@merrimack.com.

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Exosomes released from tumor-associated macrophages transfer miRNAs that induce a Treg/Th17 cell imbalance in epithelial ovarian cancer

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The immune microenvironment is crucial for epithelial ovarian cancer (EOC) progression and consists of tumor-associated macrophages (TAMs) and T lymphocytes, such as regulatory T cells (Tregs) and T helper 17 (Th17) cells. In this study, the Treg/Th17 ratio was significantly higher in EOC in situ and in metastatic peritoneal tissues than in benign ovarian tumors and benign peritoneum. The Treg/Th17 ratio was associated with histological grade and was an independent prognostic factor for overall survival of EOC patients. Based on microarray analysis of exosomes derived from TAMs, we identified miRNAs enriched in the exosomes, including miR-29a-3p and miR-21-5p. When the two miRNA mimics were transfected into CD4+ T cells, they directly suppressed STAT3 and regulated Treg/Th17 cells, inducing an imbalance, and they had a synergistic effect on STAT3 inhibition. Taken together, these results indicate that exosomes mediate the interaction between TAMs and T cells, generating an immune suppressive microenvironment that facilitates EOC progression and metastasis. These findings suggest that targeting these exosomes or their associated miRNAs might pave the way for the development of novel treatments for EOC.

Author Info: (1) Department of Gynecology and Obstetrics, Xinhua Hospital, Affiliated with Shanghai Jiao Tong University School of Medicine. (2) Department of Gynecology, Shanghai First Maternity and

Author Info: (1) Department of Gynecology and Obstetrics, Xinhua Hospital, Affiliated with Shanghai Jiao Tong University School of Medicine. (2) Department of Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine. (3) Department of Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University. (4) Obstetrics and Gynecology, Renji Hospital, Shanghai JiaoTong University. (5) Department of Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University. (6) Department of Obstetrics and Gynecology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine. (7) Department of gynecology and obstetrics, Xinhua Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine. (8) Department of Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine. (9) Department of Neurosurgery, Renji Hospital, School of Medicine, Shanghai Jiao-Tong University. (10) Department of gynecology and obstetrics, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine xipengwang@hotmail.com.

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Radiotherapy induces responses of lung cancer to CTLA-4 blockade

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Focal radiation therapy enhances systemic responses to anti-CTLA-4 antibodies in preclinical studies and in some patients with melanoma(1-3), but its efficacy in inducing systemic responses (abscopal responses) against tumors unresponsive to CTLA-4 blockade remained uncertain. Radiation therapy promotes the activation of anti-tumor T cells, an effect dependent on type I interferon induction in the irradiated tumor(4-6). The latter is essential for achieving abscopal responses in murine cancers(6). The mechanisms underlying abscopal responses in patients treated with radiation therapy and CTLA-4 blockade remain unclear. Here we report that radiation therapy and CTLA-4 blockade induced systemic anti-tumor T cells in chemo-refractory metastatic non-small-cell lung cancer (NSCLC), where anti-CTLA-4 antibodies had failed to demonstrate significant efficacy alone or in combination with chemotherapy(7,8). Objective responses were observed in 18% of enrolled patients, and 31% had disease control. Increased serum interferon-beta after radiation and early dynamic changes of blood T cell clones were the strongest response predictors, confirming preclinical mechanistic data. Functional analysis in one responding patient showed the rapid in vivo expansion of CD8 T cells recognizing a neoantigen encoded in a gene upregulated by radiation, supporting the hypothesis that one explanation for the abscopal response is radiation-induced exposure of immunogenic mutations to the immune system.

Author Info: (1) Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, USA. formenti@med.cornell.edu. (2) Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, USA

Author Info: (1) Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, USA. formenti@med.cornell.edu. (2) Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, USA. (3) Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, USA. Department of Radiation Oncology, University of California, San Francisco, CA, USA. (4) Department of Radiation Oncology, New York University School of Medicine, New York, NY, USA. (5) Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, USA. (6) Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, USA. (7) Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, USA. (8) Department of Radiology, New York University School of Medicine, New York, NY, USA. (9) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, USA. (10) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, USA. (11) Department of Pathology, New York University School of Medicine, New York, NY, USA. Genome Technology Center, Division of Advanced research Technologies, NYU Langone Health, New York, NY, USA. (12) Tisch Cancer Institute, Hematology/Oncology, Immunology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (13) Tisch Cancer Institute, Hematology/Oncology, Immunology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (14) Adaptive Biotechnologies, Seattle, WA, USA. (15) Division of Biostatistics and Epidemiology, Department of Healthcare Policy and Research, Weill Cornell Medicine, New York, NY, USA. (16) Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY, USA. (17) Department of Medicine, New York University School of Medicine, New York, NY, USA. (18) Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, USA. szd3005@med.cornell.edu. Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA. szd3005@med.cornell.edu.

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