Journal Articles

Checkpoint modulation

Cancer immunotherapeutic approaches that target stimulatory or inhibitory immune checkpoint pathways as well as immune related adverse events associated with these therapies

VISTA expression on tumor-infiltrating inflammatory cells in primary cutaneous melanoma correlates with poor disease-specific survival

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Adaptive immune responses contribute to the pathogenesis of melanoma by facilitating immune evasion. V-domain Ig suppressor of T-cell activation (VISTA) is a potent negative regulator of T-cell function and is expressed at high levels on monocytes, granulocytes, and macrophages, and at lower densities on T-cell populations within the tumor microenvironment. In this study, 85 primary melanoma specimens were selected from pathology tissue archives and immunohistochemically stained for CD3, PD-1, PD-L1, and VISTA. Pearson's correlation coefficients identified associations in expression between VISTA and myeloid infiltrate (r = 0.28, p = 0.009) and the density of PD-1+ inflammatory cells (r = 0.31, p = 0.005). The presence of VISTA was associated with a significantly worse disease-specific survival in univariate analysis (hazard ratio = 3.57, p = 0.005) and multivariate analysis (hazard ratio = 3.02, p = 0.02). Our findings show that VISTA expression is an independent negative prognostic factor in primary cutaneous melanoma and suggests its potential as an adjuvant immunotherapeutic intervention in the future.

Author Info: (1) Geisel School of Medicine at Dartmouth, Hanover, NH, USA. Department of Medicine, Santa Barbara Cottage Hospital, Santa Barbara, CA, USA. (2) Department of Pathology

Author Info: (1) Geisel School of Medicine at Dartmouth, Hanover, NH, USA. Department of Medicine, Santa Barbara Cottage Hospital, Santa Barbara, CA, USA. (2) Department of Pathology and Laboratory Medicine, Dartmouth-Hitchcock Medical Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA. (3) Biostatistics Shared Resource, Norris Cotton Cancer Center, Dartmouth-Hitchock Medical Center, Lebanon, NH, USA. (4) Department of Medicine, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA. (5) Departments of Biomedical Data Sciences, Molecular and Systems Biology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, USA. (6) Department of Microbiology and Immunology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Hanover, NH, USA. (7) Department of Surgery, Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA. (8) Department of Microbiology and Immunology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Hanover, NH, USA. (9) Roswell Park Cancer Institute, University of Buffalo, The State University of New York, Elm and Carlton, Buffalo, NY, 14263, USA. marc.ernstoff@roswellpark.org.

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Immune Checkpoint Inhibitors in the Treatment of Patients with Neuroendocrine Neoplasia

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BACKGROUND: Well-differentiated neuroendocrine neoplasms (NENs) are usually controlled by antiproliferative, local ablative and/or radionuclide therapies, whereas poorly differentiated NENs generally require cytotoxic chemotherapy. However, treatment options for patients with advanced/metastatic high-grade NENs remain limited. METHOD: Review of the literature and international congress abstracts on the efficacy and safety of immunotherapy by checkpoint inhibition in advanced/metastatic NENs. RESULTS: Evidence points to an important role of immune phenomena in the pathogenesis and treatment of neuroendocrine tumors (NETs). Programmed cell death 1 (PD-1) protein and its ligand are mainly expressed in poorly differentiated NENs. Microsatellite instability and high mutational load are more pronounced in high-grade NENs and may predict response to immunotherapy. Clinical experience of immune checkpoint blockade mainly exists for Merkel cell carcinoma, a high-grade cutaneous neuroendocrine carcinoma (NEC), which has led to approval of the anti-PD-1 antibody avelumab. In addition, there is anecdotal evidence for the efficacy of checkpoint inhibitors in large-cell lung NECs, ovarian NECs and others, including gastroenteropancreatic NENs. Currently, phase II studies investigate PDR001, pembrolizumab, combined durvalumab and tremelimumab, and avelumab treatment in patients with advanced/metastatic NENs. CONCLUSION: Immune checkpoint inhibitors are a promising therapeutic option, especially in progressive NECs or high-grade NETs with high tumor burden, microsatellite instability, and/or mutational load.

Author Info: (1) (2)

Author Info: (1) (2)

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Radiologic pseudoprogression during anti-PD1 therapy for advanced non-small cell lung cancer

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INTRODUCTION: Anti-PD1 (programmed cell death protein 1) therapy can lead to unconventional tumor responses including radiologic pseudoprogression. Here we determine the real-world incidence of radiologic pseudoprogression in advanced non-small cell lung cancer (NSCLC) and compare radiologic response criteria for disease response assessment. METHODS: Electronic medical records of all NSCLC patients receiving anti-PD1 therapy at our institution over a 3-year period were retrospectively reviewed and patients with clinically suspected radiologic pseudoprogression identified. Patients without available follow-up imaging or clinical data were excluded. Imaging examinations were then analyzed to determine if progression was confirmed on subsequent re-imaging. Tumor response assessment by the RECIST1.1, unidimensional immune-related response criteria (iRRC) and iRECIST criteria for all patients were calculated and compared. RESULTS: A total of 228 consecutive patients were started on anti-PD1 therapy over a 3-year period, of which a total of 166 were evaluable, the majority (80%) of which received nivolumab. Fifteen patients (9%) were clinically suspected to have radiologic pseudoprogression due to tumor enlargement and/or development of new lesions on CT during the first 4-6 weeks of therapy and were maintained on anti-PD1 therapy. Of these patients, 3 patients (2% of all patients) demonstrated evidence of radiologic pseudoprogression at 1(st) re-imaging. iRRC and iRECIST were more accurate in classifying radiologic pseudoprogression as non-progression; none of the 3 cases were deemed progression by iRRC or iRECIST, compared to all 3 cases called progression on RECIST1.1. CONCLUSIONS: Radiologic pseudoprogression is a clinical challenge but an uncommon occurrence in NSCLC patients receiving anti-PD1 therapy.

Author Info: (1) Department of Radiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA. Electronic address: sharyn.katz@uphs.upenn.edu. (2) Department of Radiology, University of Pennsylvania Perelman School

Author Info: (1) Department of Radiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA. Electronic address: sharyn.katz@uphs.upenn.edu. (2) Department of Radiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; Department of Radiology, Brigham and Women's Hospital, Boston, MA. (3) Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA. (4) Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA. (5) Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA. (6) Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA. (7) Department of Radiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA. (8) Department of Radiation Oncology, University of Maryland Medical Center, Baltimore, MD. (9) Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.

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Recommendations for managing PD-1 blockade in the context of allogeneic HCT in Hodgkin lymphoma: taming a necessary evil

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PD-1 blockade is an effective therapy in relapsed/refractory (R/R) classical Hodgkin Lymphoma (cHL) who have relapsed after or are ineligible for autologous hematopoietic cell transplantation (HCT). While single-agent anti-PD-1 monoclonal antibodies (mAbs) are associated with high response rates and durable remissions, available results to date suggest that a large majority of patients will eventually progress on therapy. Many of these patients are potential candidates for allogeneic HCT (allo-HCT) after receiving anti-PD-1 mAbs, and allo-HCT remains for now the only treatment with demonstrated curative potential in this setting. However, initial reports suggested that allo-HCT in this setting may be associated with increased risk of early transplant-related toxicity, likely driven by lingering effects of PD-1 blockade. Furthermore, many patients with R/R cHL who undergo allo-HCT will relapse after transplantation, most often with limited treatment options. Here again PD-1 blockade appears to yield high response rates, but with an increased risk of attendant immune toxicity. Many questions remain regarding the use of PD-1 blockade before or after allo-HCT, especially in relation to the feasibility, outcome, optimal timing, and method of allo-HCT after PD-1 blockade. Despite the scarcity of prospective data, these questions are unavoidable and must be tackled by clinicians in the routine care of patients with advanced cHL. We provide consensus recommendations of a working group based on available data and experience, in an effort to help guide treatment decisions until more definitive data are obtained.

Author Info: (1) CHRU Lille, Lille, France. (2) Dana-Farber Cancer Institute, Boston, MA, United States. (3) The Ohio State University, Columbus, OH, United States. (4) Dana-Farber Cancer

Author Info: (1) CHRU Lille, Lille, France. (2) Dana-Farber Cancer Institute, Boston, MA, United States. (3) The Ohio State University, Columbus, OH, United States. (4) Dana-Farber Cancer Institute, Boston, MA, United States. (5) CHU Rennes, Rennes, France. (6) CHRU Lille, Lille, France. (7) University of Colorado, Aurora, CO, United States bradley.haverkos@ucdenver.edu.

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VISTA expression associated with CD8 confers a favorable immune microenvironment and better overall survival in hepatocellular carcinoma

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BACKGROUND: Hepatocellular carcinoma (HCC) often arises in the setting of chronic inflammation with multiple inhibitory immune signals. V-domain Ig suppressor of T cell activation (VISTA) is identified as a novel negative checkpoint regulator. This study sought to determine the expression and prognostic value of VISTA in HCC and classify tumor microenvironments (TMEs) based on VISTA and CD8+ tumor-infiltrating lymphocytes (TILs). METHODS: The expression of VISTA and CD8 proteins was assessed in 183 HCC tissue microarrays (TMAs) by immunohistochemistry (IHC). VISTA and CD8A mRNA extracted from 372 patients with HCC in The Cancer Genome Atlas (TCGA) database was included as a validation cohort. Associations between the VISTA, clinicopathological variables, and survival were analyzed. RESULTS: VISTA expression was detected in 29.5% HCC tissues, among which 16.4% tissues were positive for tumor cells (TCs), and 16.9% tissues were positive for immune cells (ICs). VISTA expression was significantly associated with tissues with a high pathological grading (p = 0.038), without liver cirrhosis (p = 0.011), and with a high density of CD8 + TILs (p < 0.001). Kaplan-Meier curves demonstrated that patients with VISTA-positive staining in TCs (p = 0.037), but not in ICs, (p = 0.779) showed significantly prolonged overall survival (OS) than those with VISTA-negative expression. Classification of HCC TME-based VISTA and CD8 + TILs showed 4 immune subtypes: VISTA+/CD8+ (16.9%), VISTA+/CD8- (12.6%), VISTA-/CD8+ (16.4%), and VISTA-/CD8+ (54.1%). The dual positive VISTA+/CD8+ subtype showed significantly prolonged OS than other subtypes (p = 0.023). CONCLUSIONS: VISTA protein expression in HCC showed cell specific and displayed different prognosis. VISTA expression was significantly associated with CD8 + TILs, Dual positive VISTA+/CD8+ showed favorable TME and better OS.

Author Info: (1) Department of Interventional Radiology, Nanfang Hospital, Southern Medical University, 1838, North Guangzhou Avenue, Guangzhou, China. (2) Department of Interventional Radiology, Nanfang Hospital, Southern Medical

Author Info: (1) Department of Interventional Radiology, Nanfang Hospital, Southern Medical University, 1838, North Guangzhou Avenue, Guangzhou, China. (2) Department of Interventional Radiology, Nanfang Hospital, Southern Medical University, 1838, North Guangzhou Avenue, Guangzhou, China. (3) Department of Interventional Radiology, Nanfang Hospital, Southern Medical University, 1838, North Guangzhou Avenue, Guangzhou, China. (4) Department of Pathology and Laboratory Medicine, Guangdong General Hospital and Guangdong Academy of Medical Sciences, 106 Zhongshan Er Rd, Guangzhou, China. (5) Department of Pathology and Laboratory Medicine, Guangdong General Hospital and Guangdong Academy of Medical Sciences, 106 Zhongshan Er Rd, Guangzhou, China. (6) Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, 1838, North Guangzhou Avenue, Guangzhou, China. dongzy1317@foxmail.com. (7) Department of Interventional Radiology, Nanfang Hospital, Southern Medical University, 1838, North Guangzhou Avenue, Guangzhou, China. ozonetherapy@126.com.

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Expression of LLT1 and its receptor CD161 in lung cancer is associated with better clinical outcome

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Co-stimulatory and inhibitory receptors expressed by immune cells in the tumor microenvironment modulate the immune response and cancer progression. Their expression and regulation are still not fully characterized and a better understanding of these mechanisms is needed to improve current immunotherapies. Our previous work has identified a novel ligand/receptor pair, LLT1/CD161, that modulates immune responses. Here, we extensively characterize its expression in non-small cell lung cancer (NSCLC). We show that LLT1 expression is restricted to germinal center (GC) B cells within tertiary lymphoid structures (TLS), representing a new hallmark of the presence of active TLS in the tumor microenvironment. CD161-expressing immune cells are found at the vicinity of these structures, with a global enrichment of NSCLC tumors in CD161(+) CD4(+) and CD8(+) T cells as compared to normal distant lung and peripheral blood. CD161(+) CD4(+) T cells are more activated and produce Th1-cytokines at a higher frequency than their matched CD161-negative counterparts. Interestingly, CD161(+) CD4(+) T cells highly express OX40 co-stimulatory receptor, less frequently 4-1BB, and display an activated but not completely exhausted PD-1-positive Tim-3-negative phenotype. Finally, a meta-analysis revealed a positive association of CLEC2D (coding for LLT1) and KLRB1 (coding for CD161) gene expression with favorable outcome in NSCLC, independently of the size of T and B cell infiltrates. These data are consistent with a positive impact of LLT1/CD161 on NSCLC patient survival, and make CD161-expressing CD4(+) T cells ideal candidates for efficient anti-tumor recall responses.

Author Info: (1) Universite Cote d'Azur, CNRS UMR7275, Institut de Pharmacologie Moleculaire et Cellulaire (IPMC), Valbonne, France. (2) Laboratory "Immune Microenvironment and Tumors", Department "Cancer, Immunology, Immunotherapy"

Author Info: (1) Universite Cote d'Azur, CNRS UMR7275, Institut de Pharmacologie Moleculaire et Cellulaire (IPMC), Valbonne, France. (2) Laboratory "Immune Microenvironment and Tumors", Department "Cancer, Immunology, Immunotherapy", INSERM UMRS 1138, Cordeliers Research Center, Paris, France. University Pierre and Marie Curie/Paris VI, Paris, France. University Paris Descartes/Paris V, Sorbonne Paris Cite, Paris, France. (3) Laboratory "Immune Microenvironment and Tumors", Department "Cancer, Immunology, Immunotherapy", INSERM UMRS 1138, Cordeliers Research Center, Paris, France. University Pierre and Marie Curie/Paris VI, Paris, France. University Paris Descartes/Paris V, Sorbonne Paris Cite, Paris, France. (4) Laboratory "Immune Microenvironment and Tumors", Department "Cancer, Immunology, Immunotherapy", INSERM UMRS 1138, Cordeliers Research Center, Paris, France. University Pierre and Marie Curie/Paris VI, Paris, France. University Paris Descartes/Paris V, Sorbonne Paris Cite, Paris, France. (5) Laboratory "Immune Microenvironment and Tumors", Department "Cancer, Immunology, Immunotherapy", INSERM UMRS 1138, Cordeliers Research Center, Paris, France. University Pierre and Marie Curie/Paris VI, Paris, France. University Paris Descartes/Paris V, Sorbonne Paris Cite, Paris, France. Department of Pathology, Hopitaux Universitaires Paris Centre, AP-HP, Paris, France. (6) Universite Cote d'Azur, CNRS UMR7275, Institut de Pharmacologie Moleculaire et Cellulaire (IPMC), Valbonne, France. (7) Laboratory "Immune Microenvironment and Tumors", Department "Cancer, Immunology, Immunotherapy", INSERM UMRS 1138, Cordeliers Research Center, Paris, France. University Pierre and Marie Curie/Paris VI, Paris, France. University Paris Descartes/Paris V, Sorbonne Paris Cite, Paris, France. Department of Pathology, Hopitaux Universitaires Paris Centre, AP-HP, Paris, France. (8) University Paris Descartes/Paris V, Sorbonne Paris Cite, Paris, France. Department of Thoracic Surgery, Hopitaux Universitaires Paris Centre, AP-HP, Paris, France. (9) Laboratory "Immune Microenvironment and Tumors", Department "Cancer, Immunology, Immunotherapy", INSERM UMRS 1138, Cordeliers Research Center, Paris, France. Department of Pathology, Institut Mutualiste Montsouris, Paris, France. (10) Universite Cote d'Azur, CNRS UMR7275, Institut de Pharmacologie Moleculaire et Cellulaire (IPMC), Valbonne, France. (11) Laboratory "Immune Microenvironment and Tumors", Department "Cancer, Immunology, Immunotherapy", INSERM UMRS 1138, Cordeliers Research Center, Paris, France. University Pierre and Marie Curie/Paris VI, Paris, France. University Paris Descartes/Paris V, Sorbonne Paris Cite, Paris, France. (12) University of Lyon, University Lyon 1, Lyon, France. Institut du Thorax Curie-Montsouris, Institut Curie, Paris, France. (13) Thoracic Department, Institut du Thorax Curie-Montsouris, Institut Mutualiste Montsouris, Paris, France. (14) Thoracic Department, Institut du Thorax Curie-Montsouris, Institut Mutualiste Montsouris, Paris, France. Paris 13 University, Sorbonne Paris Cite, Faculty of Medicine SMBH, Bobigny, France. (15) Laboratory "Immune Microenvironment and Tumors", Department "Cancer, Immunology, Immunotherapy", INSERM UMRS 1138, Cordeliers Research Center, Paris, France. University Pierre and Marie Curie/Paris VI, Paris, France. University Paris Descartes/Paris V, Sorbonne Paris Cite, Paris, France. (16) Laboratory "Immune Microenvironment and Tumors", Department "Cancer, Immunology, Immunotherapy", INSERM UMRS 1138, Cordeliers Research Center, Paris, France. University Pierre and Marie Curie/Paris VI, Paris, France. University Paris Descartes/Paris V, Sorbonne Paris Cite, Paris, France.

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PD-L1 expression in medulloblastoma: an evaluation by subgroup

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Background: This study evaluated the expression of PD-L1 and markers of immune mediated resistance in human medulloblastoma (MB), the most common malignant pediatric brain tumor. Results: Overall levels of PD-L1 in human MB were low; however, some cases demonstrated robust focal expression associated with increased immune infiltrates. The case with highest PD-L1 expression was a sonic hedgehog (SHH) MB. In cell lines, SHH MB, which are low-MYC expressing, demonstrated both constitutive and inducible expression of PD-L1 while those in Group 3/4 that expressed high levels of MYC had only inducible expression. In vitro, IFN-gamma robustly stimulated the expression of PD-L1 in all cell lines while radiation induced variable expression. Forced high MYC expression did not significantly alter PD-L1. Methods: Human MB tumor samples were evaluated for expression of PD-L1 and immune cell markers in relation to molecular subgroup assignment. PD-L1 expression was functionally analyzed under conditions of interferon gamma (IFN-gamma), radiation, and MYC overexpression. Conclusions: MB expresses low levels of PD-L1 facilitating immune escape. Importantly, TH1 cytokine stimulation appears to be the most potent inducer of PD-L1 expression in vitro suggesting that an inflamed tumor microenvironment is necessary for PD-1 pathway activation in this tumor.

Author Info: (1) Johns Hopkins School of Medicine, Sidney Kimmel Cancer Center, Division of Pediatric Oncology, Baltimore, MD, USA. (2) Johns Hopkins School of Medicine, Sidney Kimmel

Author Info: (1) Johns Hopkins School of Medicine, Sidney Kimmel Cancer Center, Division of Pediatric Oncology, Baltimore, MD, USA. (2) Johns Hopkins School of Medicine, Sidney Kimmel Cancer Center, Division of Cancer Immunology, Baltimore, MD, USA. (3) Johns Hopkins School of Medicine, Sidney Kimmel Cancer Center, Division of Pediatric Oncology, Baltimore, MD, USA. (4) Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN, USA. (5) Johns Hopkins School of Medicine, Department of Pathobiology, Baltimore, MD, USA. (6) Johns Hopkins School of Medicine, Department of Ophthalmology, Baltimore, MD, USA. (7) Johns Hopkins School of Medicine, Sidney Kimmel Cancer Center, Division of Cancer Biology, Baltimore, MD, USA. (8) Johns Hopkins School of Medicine, Department of Pathology, Division of Kidney and Urologic Pathology, Baltimore, MD, USA. (9) Children's Hospital of Philadelphia, Department of Pathology and Laboratory Medicine, Philadelphia, PA, USA. (10) Johns Hopkins School of Medicine, Department of Dermatology, Division of Dermatologic Pathology and Oral Pathology, Baltimore, MD, USA. (11) Johns Hopkins School of Medicine, Department of Dermatology, Division of Dermatologic Pathology and Oral Pathology, Baltimore, MD, USA. (12) In Jackson, MS, USA. (13) Johns Hopkins School of Medicine, Department of Pathology, Division of Kidney and Urologic Pathology, Baltimore, MD, USA. (14) Johns Hopkins School of Medicine, Sidney Kimmel Cancer Center, Division of Pediatric Oncology, Baltimore, MD, USA. Johns Hopkins School of Medicine, Department of Pathology, Division of Neuropathology, Baltimore, MD, USA. (15) Johns Hopkins School of Medicine, Sidney Kimmel Cancer Center, Division of Pediatric Oncology, Baltimore, MD, USA. (16) Johns Hopkins School of Medicine, Department of Pathology, Division of Neuropathology, Baltimore, MD, USA. (17) Johns Hopkins School of Medicine, Department of Pathology, Division of Neuropathology, Baltimore, MD, USA. (18) Children's Hospital of Philadelphia, Department of Pathology and Laboratory Medicine, Philadelphia, PA, USA. (19) Johns Hopkins School of Medicine, Department of Dermatology, Division of Dermatologic Pathology and Oral Pathology, Baltimore, MD, USA. (20) Johns Hopkins School of Medicine, Sidney Kimmel Cancer Center, Division of Cancer Immunology, Baltimore, MD, USA. (21) Columbia University Medical Center, Division of Hematology/Oncology, New York, NY, USA. (22) Johns Hopkins School of Medicine, Department of Neurosurgery, Division of Neurosurgical Oncology, Baltimore, MD, USA.

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CD200fc enhances anti-tumoral immune response and inhibits visceral metastasis of breast carcinoma

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CD200 is a widely expressed cell surface glycoprotein that inhibits excessive inflammation in autoimmunity, transplantation, and viral infections. We previously observed that visceral metastasis of highly aggressive and inflammatory 4THM breast carcinoma cells was markedly decreased in CD200 transgenic mice. The goal of this study was to determine whether exogenous exposure to CD200fc mimics the effects of endogenously over expressed CD200. Female BALB/c mice were injected with CD200fc two times a week for five times. Injection was started two days after orthotopic injection of 4THM cells. Tumor infiltrating Gr1+Cd11b+ cells were decreased while CD8+ cells were increased in CD200fc-treated animals. CD200fc injection significantly decreased lung and liver metastasis and the growth of primary tumors. CD200fc injection enhanced the tumor-induced IFN-g response while suppressing the IL-10 response. We observed excessive basal IL-6 secretion in MLC which was significantly decreased in CD200fc treated mice 12 days after injection of 4TM cells. These results are in accord with previous data from CD200 transgenic mice, and demonstrate for the first time that CD200 analogues might have therapeutic potential in the treatment of aggressive breast carcinoma which induces excessive systemic inflammation.

Author Info: (1) Department of Medical Pharmacology, Akdeniz University, School of Medicine, Antalya, Turkey. (2) Histology and Embryology, Akdeniz University, School of Medicine, Antalya, Turkey. (3) University

Author Info: (1) Department of Medical Pharmacology, Akdeniz University, School of Medicine, Antalya, Turkey. (2) Histology and Embryology, Akdeniz University, School of Medicine, Antalya, Turkey. (3) University Health Network, Toronto General Hospital, Toronto, Canada. (4) Department of Medical Pharmacology, Akdeniz University, School of Medicine, Antalya, Turkey. (5) Department of Medical Pharmacology, Akdeniz University, School of Medicine, Antalya, Turkey. (6) University Health Network, Toronto General Hospital, Toronto, Canada.

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A pilot study of durvalumab and tremelimumab and immunogenomic dynamics in metastatic breast cancer

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Immune checkpoint inhibitors produce modest responses in metastatic breast cancer, however, combination approaches may improve responses. A single arm pilot study was designed to determine the overall response rate (ORR) of durvalumab and tremelimumab, and evaluate immunogenomic dynamics in metastatic endocrine receptor (ER) positive or triple negative breast cancer (TNBC). Simon two-stage design indicated at least four responses from the first 18 patients were needed to proceed with the second stage. T-cell receptor (TCR) sequencing and immune-gene expression profiling were conducted at baseline and two months, whole exome sequencing was conducted at baseline. Eighteen evaluable patients were accrued (11 ER-positive; seven TNBC). Only three patients had a response (ORR = 17%), thus the study did not proceed to the second stage. Responses were only observed in patients with TNBC (ORR = 43%). Responders versus non-responders had upregulation of CD8, granzyme A, and perforin 1 gene expression, and higher mutational and neoantigen burden. Patients with TNBC had an oligoclonal shift of the most abundant TCR-beta clonotypes compared to those with ER-positive disease, p = 0.004. We conclude responses are low in unselected metastatic breast cancer, however, higher rates of clinical benefit were observed in TNBC. Immunogenomic dynamics may help identify phenotypes most likely to respond to immunotherapy.

Author Info: (1) Johns Hopkins, Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA. (2) The University of Chicago, Department of Medicine, Chicago, Illinois, USA. (3) The University

Author Info: (1) Johns Hopkins, Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA. (2) The University of Chicago, Department of Medicine, Chicago, Illinois, USA. (3) The University of Chicago, Department of Medicine, Chicago, Illinois, USA. (4) The University of Chicago, Department of Medicine, Chicago, Illinois, USA. (5) Northwestern University, Robert H. Lurie Comprehensive Cancer Center, Chicago, Illinois, USA. (6) Northwestern University, Robert H. Lurie Comprehensive Cancer Center, Chicago, Illinois, USA. (7) Northwestern University, Robert H. Lurie Comprehensive Cancer Center, Chicago, Illinois, USA. (8) Northwestern University, Robert H. Lurie Comprehensive Cancer Center, Chicago, Illinois, USA. (9) Northwestern University, Robert H. Lurie Comprehensive Cancer Center, Chicago, Illinois, USA. (10) Northwestern University, Robert H. Lurie Comprehensive Cancer Center, Chicago, Illinois, USA. (11) Northwestern University, Robert H. Lurie Comprehensive Cancer Center, Chicago, Illinois, USA. (12) Northwestern University, Robert H. Lurie Comprehensive Cancer Center, Chicago, Illinois, USA. (13) Northwestern University, Robert H. Lurie Comprehensive Cancer Center, Chicago, Illinois, USA. (14) Northwestern University, Robert H. Lurie Comprehensive Cancer Center, Chicago, Illinois, USA. (15) Northwestern University, Robert H. Lurie Comprehensive Cancer Center, Chicago, Illinois, USA. (16) The University of Chicago, Department of Medicine, Chicago, Illinois, USA. The University of Chicago, Department of Surgery, Chicago, Illinois, USA. (17) Northwestern University, Robert H. Lurie Comprehensive Cancer Center, Chicago, Illinois, USA.

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Merkel cell carcinoma expresses the immunoregulatory ligand CD200 and induces immunosuppressive macrophages and regulatory T cells

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Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer that responds to PD-1/PD-L1 immune checkpoint inhibitors. CD200 is another checkpoint modulator whose receptor is found on tumor-promoting myeloid cells, including M2 macrophages. We found high CD200 mRNA expression in MCC tumors, and CD200 immunostaining was demonstrated on 95.5% of MCC tumors. CD200R-expressing myeloid cells were present in the MCC tumor microenvironment. MCC-associated macrophages had a higher average CD163:CD68 staining ratio (2.67) than controls (1.13), indicating an immunosuppressive M2 phenotype. Accordingly, MCC tumors contained increased densities of FOXP3(+) regulatory T-cells. Intravenous administration of blocking anti-CD200 antibody to MCC xenograft mice revealed specific targeting of drug to tumor. In conclusion, MCC are highly CD200 positive and associated with immunosuppressive M2 macrophages and regulatory T-cells. As anti-CD200 antibody effectively targets CD200 on MCC tumor cells in vivo, this treatment may provide a novel immunotherapy for MCC independent of PD-1/PD-L1 blockade.

Author Info: (1) Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of

Author Info: (1) Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany. Department of Dermatology, Heidelberg University Hospital, Heidelberg, Germany. (2) Department of Dermatology, Heidelberg University Hospital, Heidelberg, Germany. (3) Department of Dermatology, Heidelberg University Hospital, Heidelberg, Germany. (4) Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, USA. (5) National Center for Tumor Diseases and Department of Dermatology, University Hospital Heidelberg, Ruprecht-Karl University of Heidelberg, Heidelberg, Germany. (6) Tissue Bank of the National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg, Germany. Institute of Pathology, Ruprecht-Karl University of Heidelberg, Heidelberg, Germany. (7) Tissue Bank of the National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg, Germany. (8) Dermatology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, USA. (9) Dermatology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, USA. (10) Dermatology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, USA.

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