Journal Articles

Immune monitoring

Techniques to monitor the immune response to cancer immunotherapy, to study immune cell interactions and to extend knowledge related to the induction and mechanisms of an immune response

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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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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Targeted overexpression of prostacyclin synthase inhibits lung tumor progression by recruiting CD4+ T lymphocytes in tumors that express MHC class II

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Lung-specific overexpression of prostacyclin synthase (PGIS) decreases tumor initiation in murine lung cancer models. Prostacyclin analogs prevent lung tumor formation in mice and reverse bronchial dysplasia in former smokers. However, the effect of prostacyclin on lung cancer progression has not been well studied. We investigated the effects of pulmonary PGIS overexpression in an orthotopic immunocompetent mouse model of lung cancer using two murine lung cancer cell lines. Pulmonary PGIS overexpression significantly inhibited CMT167 lung tumor growth, increased CXCL9 expression, and increased CD4+ tumor-infiltrating lymphocytes. Immunodepletion of CD4+ T cells abolished the inhibitory effect of pulmonary PGIS overexpression on CMT167 lung tumor growth. In contrast, pulmonary PGIS overexpression failed to inhibit growth of a second murine lung cancer cell line, Lewis Lung Carcinoma (LLC) cells, and failed to increase CXCL9 expression or CD4+ T lymphocytes in LLC lung tumors. Transcriptome profiling of CMT167 cells and LLC cells recovered from tumor-bearing mice demonstrated that in vivo, CMT167 cells but not LLC cells express MHC class II genes and cofactors necessary for MHC class II processing and presentation. These data demonstrate that prostacyclin can inhibit lung cancer progression and suggest that prostacyclin analogs may serve as novel immunomodulatory agents in a subset of lung cancer patients. Moreover, expression of MHC Class II by lung cancer cells may represent a biomarker for response to prostacyclin.

Author Info: (1) Department of Medicine, Veterans Affairs Medical Center, Denver, CO, USA. Departments of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. (2) Departments

Author Info: (1) Department of Medicine, Veterans Affairs Medical Center, Denver, CO, USA. Departments of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. (2) Departments of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. (3) Departments of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. (4) Departments of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. (5) Departments of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. (6) Departments of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. (7) Departments of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. (8) Departments of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. (9) Departments of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. (10) Department of Medicine, Veterans Affairs Medical Center, Denver, CO, USA. Departments of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. (11) Departments of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. Departments of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. (12) Departments of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. (13) Departments of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. Departments of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.

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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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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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Circulating tumor DNA evaluated by Next-Generation Sequencing is predictive of tumor response and prolonged clinical benefit with nivolumab in advanced non-small cell lung cancer

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Nivolumab is an anti-PD1 antibody, given in second-line or later treatment in advanced non-small cell lung cancer (NSCLC). The objective of this study was to describe the predictive value of circulating tumor DNA (ctDNA) on the efficacy of nivolumab in advanced NSCLC. We prospectively included all consecutive patients with advanced NSCLC treated with nivolumab in our Department between June 2015 and October 2016. Plasma samples were obtained before the first injection of nivolumab and at the first tumor evaluation with nivolumab. ctDNA was analyzed by Next-Generation Sequencing (NGS), and the predominant somatic mutation was followed for each patient and correlated with tumor response, clinical benefit (administration of nivolumab for more than 6 months), and progression-free survival (PFS). Of 23 patients, 15 had evaluable NGS results at both times of analysis. ctDNA concentration at the first tumor evaluation and ctDNA change correlated with tumor response, clinical benefit and PFS. ROC curve analyses showed good diagnostic performances for tumor response and clinical benefit, both for ctDNA concentration at the first tumor evaluation (tumor response: positive predictive value (PPV) at 100.0% and negative predictive value (NPV) at 71.0%; clinical benefit: PPV at 83.3% and NPV 77.8%) and the ctDNA change (tumor response: PPV 100.0% and NPV 62.5%; clinical benefit: PPV 100.0% and NPV 80.0%). Patients without ctDNA concentration increase >9% at 2 months had a long-term benefit of nivolumab. In conclusion, NGS analysis of ctDNA allows the early detection of tumor response and long-term clinical benefit with nivolumab in NSCLC.

Author Info: (1) Department of Respiratory Diseases and Thoracic Oncology, APHP - Ambroise Pare Hospital, Boulogne-Billancourt, France. EA4340, Biomarqueursen Cancerologie et Onco-Hematologie, UVSQ, Paris-Saclay University, Boulogne-Billancourt, France

Author Info: (1) Department of Respiratory Diseases and Thoracic Oncology, APHP - Ambroise Pare Hospital, Boulogne-Billancourt, France. EA4340, Biomarqueursen Cancerologie et Onco-Hematologie, UVSQ, Paris-Saclay University, Boulogne-Billancourt, France. (2) INSERM UMR-S1147, CNRS SNC 5014, Saints-Peres Research Center, 45 rue des Saints-Peres Paris-Descartes University, Sorbonne Paris Cite University, Paris, France. Department of Molecular Biology, Georges Pompidou European Hospital, 20 rue Leblanc, Assistance Publique-Hopitaux de Paris, Paris, France. (3) Department of Respiratory Diseases and Thoracic Oncology, APHP - Ambroise Pare Hospital, Boulogne-Billancourt, France. (4) EA4340, Biomarqueursen Cancerologie et Onco-Hematologie, UVSQ, Paris-Saclay University, Boulogne-Billancourt, France. Department of Pathology, APHP - Ambroise Pare Hospital, Boulogne-Billancourt, France. (5) Department of Respiratory Diseases and Thoracic Oncology, APHP - Ambroise Pare Hospital, Boulogne-Billancourt, France. (6) Department of Respiratory Diseases and Thoracic Oncology, APHP - Ambroise Pare Hospital, Boulogne-Billancourt, France. (7) Department of Respiratory Diseases and Thoracic Oncology, APHP - Ambroise Pare Hospital, Boulogne-Billancourt, France. (8) EA4340, Biomarqueursen Cancerologie et Onco-Hematologie, UVSQ, Paris-Saclay University, Boulogne-Billancourt, France. Department of Pathology, APHP - Ambroise Pare Hospital, Boulogne-Billancourt, France. (9) EA4340, Biomarqueursen Cancerologie et Onco-Hematologie, UVSQ, Paris-Saclay University, Boulogne-Billancourt, France. Department of Pathology, APHP - Ambroise Pare Hospital, Boulogne-Billancourt, France. (10) INSERM UMR-S1147, CNRS SNC 5014, Saints-Peres Research Center, 45 rue des Saints-Peres Paris-Descartes University, Sorbonne Paris Cite University, Paris, France. Department of Molecular Biology, Georges Pompidou European Hospital, 20 rue Leblanc, Assistance Publique-Hopitaux de Paris, Paris, France. (11) Department of Respiratory Diseases and Thoracic Oncology, APHP - Ambroise Pare Hospital, Boulogne-Billancourt, France. EA4340, Biomarqueursen Cancerologie et Onco-Hematologie, UVSQ, Paris-Saclay University, Boulogne-Billancourt, France.

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Development of anti-drug antibodies is associated with shortened survival in patients with metastatic melanoma treated with ipilimumab

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Introduction: Checkpoint inhibitors, including the CTLA-4 blocking antibody ipilimumab, have become the new standard therapy for many metastatic cancers. Development of anti-drug antibodies (ADAs) after treatment with other biopharmaceuticals has been thoroughly described, but the induction of ADAs after treatment with checkpoint inhibitors has been inadequately investigated. In this retrospective study, we relate ipilimumab serum levels and anti-ipilimumab antibody levels to clinical outcomes in patients with metastatic melanoma (MM). Method: Serum samples from 31 patients with MM were analyzed for serum levels of ipilimumab and ADAs to ipilimumab at baseline, and before the 2(nd) and 4(th) infusion using an in-house bead-based assay. The results were correlated with progression-free survival (PFS) and overall survival (OS). Results: Low serum levels of ipilimumab before the 2(nd) infusion correlated significantly with a shorter OS (p = 0.01) and PFS (p = 0.02). Eight patients (26%) were ADA-positive at either timepoint. ADA positivity correlated significantly with a shorter OS (p = 0.03) with a hazard ratio (HR) of 3.0 (95% CI: 1.2-7.8). Four of 8 ADA-positive patients (50%) discontinued therapy before the 4(th) infusion due to disease progression, compared to three of 23 (13%) ADA-negative patients. Conclusion: We confirm that low serum levels of ipilimumab are associated with a shortened OS, and we show for the first time that ADAs to ipilimumab are associated with shorter OS in patients with MM.

Author Info: (1) Institute for Inflammation Research, Center for Rheumatology and Spine Diseases, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. Center for Cancer Immune Therapy, Department of Oncology

Author Info: (1) Institute for Inflammation Research, Center for Rheumatology and Spine Diseases, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. Center for Cancer Immune Therapy, Department of Oncology and Hematology, Copenhagen University Hospital, Herlev, Denmark. (2) Institute for Inflammation Research, Center for Rheumatology and Spine Diseases, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. (3) Center for Cancer Immune Therapy, Department of Oncology and Hematology, Copenhagen University Hospital, Herlev, Denmark. (4) Department of Oncology, Odense University Hospital, Odense, Denmark. (5) Center for Cancer Immune Therapy, Department of Oncology and Hematology, Copenhagen University Hospital, Herlev, Denmark. (6) Institute for Inflammation Research, Center for Rheumatology and Spine Diseases, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

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Prognosis of ovarian cancer is associated with effector memory CD8(+) T cell accumulation in ascites, CXCL9 levels and activation-triggered signal transduction in T cells

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The accumulation of intratumoral CD8(+) T cells is associated with the survival of high grade serous ovarian carcinoma patients, but it is unclear which CD8(+) T cell subsets contribute to this effect and how they are affected by the peritoneal tumor microenvironment. Here, we provide evidence for a functional link between long relapse-free survival, accumulation of CD8(+) effector memory T (TEM) cells in peritoneal effusion (ascites), and the level of the CD8(+) TEM attracting chemokine CXCL9, produced by macrophages as a major source. We also propose a novel mechanism by which the tumor microenvironment could contribute to T cell dysfunction and shorter survival, i.e., diminished expression levels of essential signaling proteins, including STAT5B, PLCgamma1 and NFATc2. CD8(+) TEM cells in ascites, CXCL9 levels and the expression of crucial signal transduction proteins may therefore be important biomarkers to gauge the efficiency of immune therapies and potentially represent therapeutic targets.

Author Info: (1) Institute of Molecular Biology and Tumor Research, Center for Tumor Biology and Immunology, Philipps University Marburg, Marburg, Germany. (2) Clinic for Gynecology, Gynecological Oncology

Author Info: (1) Institute of Molecular Biology and Tumor Research, Center for Tumor Biology and Immunology, Philipps University Marburg, Marburg, Germany. (2) Clinic for Gynecology, Gynecological Oncology and Gynecological Endocrinology, Center for Tumor Biology and Immunology (ZTI), Philipps University Marburg, Marburg, Germany. (3) FACS Core Facility, Biomedical Research Center, Philipps University Marburg, Marburg, Germany. Institute of Medical Microbiology and Hygiene, Biomedical Research Center, Philipps University Marburg, Marburg, Germany. (4) Institute of Molecular Biology and Tumor Research, Center for Tumor Biology and Immunology, Philipps University Marburg, Marburg, Germany. (5) Department of Gynecology and Obstetrics, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. (6) Department of Gynecology and Obstetrics, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. (7) Clinic for Gynecology, Gynecological Oncology and Gynecological Endocrinology, University Hospital of Giessen and Marburg (UKGM), Marburg, Germany. (8) Clinic for Gynecology, Gynecological Oncology and Gynecological Endocrinology, University Hospital of Giessen and Marburg (UKGM), Marburg, Germany. (9) Institute of Pharmacology, Biochemical-Pharmacological Center (BPC), Philipps University Marburg, Marburg, Germany. Department of Pharmacology, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany. (10) Institute of Molecular Biology and Tumor Research, Center for Tumor Biology and Immunology, Philipps University Marburg, Marburg, Germany. (11) Institute of Medical Microbiology and Hygiene, Biomedical Research Center, Philipps University Marburg, Marburg, Germany.

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Myeloid-derived macrophages and secreted HSP90alpha induce pancreatic ductal adenocarcinoma development

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We detected a significant elevation of serum HSP90alpha levels in pancreatitis patients and even more in pancreatic ductal adenocarcinoma (PDAC) patients. However, there was no significant difference in the serum HSP90alpha levels between patients with early-stage and late-stage PDAC. To study whether elevation of serum HSP90alpha levels occurred early during PDAC development, we used LSL-KrasG12D/Pdx1-Cre transgenic mice as a studying model. Elevated serum HSP90alpha levels were detected before PDAC formation and an extracellular HSP90alpha (eHSP90alpha) inhibitor effectively prevented PDAC development. Both serum HSP90alpha level and pancreatic lesion were suppressed when the mice were administered a CD11b-antagonizing antibody, suggesting that CD11b(+)-myeloid cells were associated with eHSP90alpha levels and pancreatic carcinogenesis. Consistently, in CD11b-DTR-EGFP transgenic mouse model with CD11b(+)-myeloid cells depletion, serum HSP90alpha levels were suppressed and Panc-02 cell grafts failed to develop tumors. Macrophages and granulocytes are two common tissue-infiltrating CD11b(+)-myeloid cells. Duplex in situ hybridization assays suggested that macrophages were predominant HSP90alpha-expressing CD11b(+)-myeloid cells during PDAC development. Immunohistochemical and immunohistofluorescent staining results revealed that HSP90alpha-expressing cells included not only macrophages but also pancreatic ductal epithelial (PDE) cells. Cell culture studies also indicated that eHSP90alpha could be produced by macrophages and macrophage-stimulated PDE cells. Macrophages not only secreted significant amount of HSP90alpha, but also secreted interleukin-6 and interleukin-8 to induce a JAK2-STAT3 signaling axis in PDE cells, stimulating them to express and secrete HSP90alpha. eHSP90alpha further promoted cellular epithelial-mesenchymal transition, migration, and invasion in PDE cells. Besides myeloid cells, eHSP90alpha can be potentially taken as a target to suppress PDAC pathogenesis.

Author Info: (1) National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan. (2) National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan. (3)

Author Info: (1) National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan. (2) National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan. (3) Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, and School of Medicine, National Yang-Ming University, Taipei, Taiwan. (4) National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan. (5) National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan. (6) National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan. (7) National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan. (8) National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan. (9) Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, and School of Medicine, National Yang-Ming University, Taipei, Taiwan. (10) National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan. (11) National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan. Department of Biochemistry, School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.

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