Immune cell biology

Proceedings of the National Academy of Sciences of the United States of America - Open Access

TRIM21 mediates antibody inhibition of adenovirus-based gene delivery and vaccination

(1) Bottermann M (2) Foss S (3) van Tienen LM (4) Vaysburd M (5) Cruickshank J (6) O'Connell K (7) Clark J (8) Mayes K (9) Higginson K (10) Hirst JC (11) McAdam MB (12) Slodkowicz G (13) Hutchinson E (14) Kozik P (15) Andersen JT (16) James LC

Adenovirus has enormous potential as a gene-therapy vector, but preexisting immunity limits its widespread application. What is responsible for this immune block is unclear because antibodies potently inhibit transgene expression without impeding gene transfer into target cells. Here we show that antibody prevention of adenoviral gene delivery in vivo is mediated by the cytosolic antibody receptor TRIM21. Genetic KO of TRIM21 or a single-antibody point mutation is sufficient to restore transgene expression to near-naive immune levels. TRIM21 is also responsible for blocking cytotoxic T cell induction by vaccine vectors, preventing a protective response against subsequent influenza infection and an engrafted tumor. Furthermore, adenoviral preexisting immunity can lead to an augmented immune response upon i.v. administration of the vector. Transcriptomic analysis of vector-transduced tissue reveals that TRIM21 is responsible for the specific up-regulation of hundreds of immune genes, the majority of which are components of the intrinsic or innate response. Together, these data define a major mechanism underlying the preimmune block to adenovirus gene therapy and demonstrate that TRIM21 efficiently blocks gene delivery in vivo while simultaneously inducing a rapid program of immune transcription.

Author Info: (1) Protein and Nucleic Acid Chemistry Division, Medical Research Council, Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom. (2) Department of Biosciences, Centre for Immune Regulation, University of Oslo, N-0316 Oslo, Norway. Department of Immunology, Centre for Immune Regulation, Oslo University Hospital, N-0372 Oslo, Norway. Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, N-0372 Oslo, Norway. (3) Protein and Nucleic Acid Chemistry Division, Medical Research Council, Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom. (4) Protein and Nucleic Acid Chemistry Division, Medical Research Council, Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom. (5) Protein and Nucleic Acid Chemistry Division, Medical Research Council, Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom. (6) Protein and Nucleic Acid Chemistry Division, Medical Research Council, Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom. (7) Protein and Nucleic Acid Chemistry Division, Medical Research Council, Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom. (8) Protein and Nucleic Acid Chemistry Division, Medical Research Council, Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom. (9) Protein and Nucleic Acid Chemistry Division, Medical Research Council, Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom. (10) MRC-University of Glasgow Centre for Virus Research, Glasgow G61 1QH, United Kingdom. (11) Department of Immunology, Centre for Immune Regulation, Oslo University Hospital, N-0372 Oslo, Norway. (12) Protein and Nucleic Acid Chemistry Division, Medical Research Council, Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom. (13) MRC-University of Glasgow Centre for Virus Research, Glasgow G61 1QH, United Kingdom. (14) Protein and Nucleic Acid Chemistry Division, Medical Research Council, Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom. (15) Department of Biosciences, Centre for Immune Regulation, University of Oslo, N-0316 Oslo, Norway. Department of Immunology, Centre for Immune Regulation, Oslo University Hospital, N-0372 Oslo, Norway. Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, N-0372 Oslo, Norway. (16) Protein and Nucleic Acid Chemistry Division, Medical Research Council, Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom; lcj@mrc-lmb.cam.ac.uk.

Citation: Proc Natl Acad Sci U S A 2018 Sep 12 Epub09/12/2018

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/30209217

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Chemotherapy Combines Effectively with Anti-PD-L1 Treatment and Can Augment Antitumor Responses

(1) Cubas R (2) Moskalenko M (3) Cheung J (4) Yang M (5) McNamara E (6) Xiong H (7) Hoves S (8) Ries CH (9) Kim J (10) Gould S

Journal of immunology

(1) Cubas R (2) Moskalenko M (3) Cheung J (4) Yang M (5) McNamara E (6) Xiong H (7) Hoves S (8) Ries CH (9) Kim J (10) Gould S

Journal of immunology

Immunotherapy with checkpoint inhibitors has proved to be highly effective, with durable responses in a subset of patients. Given their encouraging clinical activity, checkpoint inhibitors are increasingly being tested in clinical trials in combination with chemotherapy. In many instances, there is little understanding of how chemotherapy might influence the quality of the immune response generated by checkpoint inhibitors. In this study, we evaluated the impact of chemotherapy alone or in combination with anti-PD-L1 in a responsive syngeneic tumor model. Although multiple classes of chemotherapy treatment reduced immune cell numbers and activity in peripheral tissues, chemotherapy did not antagonize but in many cases augmented the antitumor activity mediated by anti-PD-L1. This dichotomy between the detrimental effects in peripheral tissues and enhanced antitumor activity was largely explained by the reduced dependence on incoming cells for antitumor efficacy in already established tumors. The effects of the various chemotherapies were also agent specific, and synergy with anti-PD-L1 was achieved by different mechanisms that ultimately helped establish a new threshold for response. These results rationalize the combination of chemotherapy with immunotherapy and suggest that, despite the negative systemic effects of chemotherapy, effective combinations can be obtained through distinct mechanisms acting within the tumor.

Author Info: (1) Genentech, South San Francisco, CA 94080; and cubasr@gene.com. (2) Genentech, South San Francisco, CA 94080; and. (3) Genentech, South San Francisco, CA 94080; and

Author Info: (1) Genentech, South San Francisco, CA 94080; and cubasr@gene.com. (2) Genentech, South San Francisco, CA 94080; and. (3) Genentech, South San Francisco, CA 94080; and. (4) Genentech, South San Francisco, CA 94080; and. (5) Genentech, South San Francisco, CA 94080; and. (6) Genentech, South San Francisco, CA 94080; and. (7) Roche Pharmaceutical Research and Early Development, Roche Innovation Center Munich, 82377 Penzberg, Germany. (8) Roche Pharmaceutical Research and Early Development, Roche Innovation Center Munich, 82377 Penzberg, Germany. (9) Genentech, South San Francisco, CA 94080; and. (10) Genentech, South San Francisco, CA 94080; and.

Citation: J Immunol 2018 Sep 12 Epub09/12/2018

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/30209192

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B-cell receptor-mediated NFATc1 activation induces IL-10/STAT3/PD-L1 signaling in diffuse large B-cell lymphoma

(1) Li L (2) Zhang J (3) Chen J (4) Xu-Monette ZY (5) Miao Y (6) Xiao M (7) Young KH (8) Wang S (9) Medeiros LJ (10) Wang M (11) Ford RJ (12) Pham LV

(1) Li L (2) Zhang J (3) Chen J (4) Xu-Monette ZY (5) Miao Y (6) Xiao M (7) Young KH (8) Wang S (9) Medeiros LJ (10) Wang M (11) Ford RJ (12) Pham LV

Knowledge of PD-L1 expression and its regulation in B-cell lymphoma cells is limited. Investigating mechanisms that control PD-L1 expression in B-cell lymphoma cells might identify biomarkers that predict the efficacy of immunotherapy with anti-PD-1/PD-L1 antibodies. In addition, identification of mechanisms that regulate PD-L1 may also identify molecules that can be targeted to improve the clinical efficacy of immune checkpoint inhibitors. In this study, we used proteomic approaches and patient-derived B-cell lymphoma cell lines to investigate mechanisms that regulate PD-L1 expression. We found that PD-L1 expression, particularly in non-germinal center B cell-derived diffuse large B-cell lymphoma (DLBCL), is controlled and regulated by several interactive signaling pathways, including the B-cell receptor (BCR) and JAK2/STAT3 signaling pathways. We found in PD-L1-positive B-cell lymphoma cells that BCR-mediated NFATc1 activation up-regulates IL-10 chemokine expression. Released IL-10 activates the JAK2/STAT3 pathway, leading to STAT3-induced PD-L1 expression. IL-10 antagonist antibody abrogates IL-10/STAT3 signaling and PD-L1 protein expression. We also found that BCR pathway inhibition by BTK inhibitors (ibrutinib, acalabrutinib, and BGB-3111) blocks both NFATc1 and STAT3 activation, thereby inhibiting IL-10 and PD-L1 expression. Finally, we validated the PD-L1 signaling network in two primary DLBCL cohorts, consisting of 428 and 350 cases and showed significant correlations between IL-10, STAT3, and PD-L1. Thus, our findings reveal a complex signaling network regulating PD-L1 expression in B-cell lymphoma cells and suggest that PD-L1 expression can be modulated by small molecule inhibitors to potentiate immunotherapies.

Author Info: (1) Department of Hematology, The Second Hospital of Dalian Medical University, Dalian, China. (2) Department of Hematopathology, The University of Texas MD Anderson Cancer Center

Author Info: (1) Department of Hematology, The Second Hospital of Dalian Medical University, Dalian, China. (2) Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (3) Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (4) Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (5) Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China. (6) Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (7) Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (8) Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (9) Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (10) Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (11) Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (12) Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States; lvpham@mdanderson.org.

Citation: Blood 2018 Sep 12 Epub09/12/2018

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/30209121

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Murine Pre-B cell ALL induces T cell dysfunction not fully reversed by introduction of a chimeric antigen receptor

(1) Qin H (2) Ishii K (3) Nguyen S (4) Su PP (5) Burk CR (6) Kim BH (7) Duncan BB (8) Tarun S (9) Shah NN (10) Kohler ME (11) Fry TJ

(1) Qin H (2) Ishii K (3) Nguyen S (4) Su PP (5) Burk CR (6) Kim BH (7) Duncan BB (8) Tarun S (9) Shah NN (10) Kohler ME (11) Fry TJ

Adoptive transfer of patient-derived T cells modified to express chimeric antigen receptors (CART) has demonstrated dramatic success in relapsed/refractory pre-B cell ALL but response and durability of remission requires exponential CART expansion and persistence. Tumors are known to affect T cell function but this has not been well studied in ALL and in the context of CAR expression. Using TCF3/PBX1 and MLL-AF4-driven murine ALL models, we assessed the impact of progressive ALL on T cell function in vivo. Vaccines protect against TCF3/PBX1.3 but were ineffective when administered after leukemia injection suggesting immunosuppression induced early during ALL progression. T cells from leukemia-bearing mice exhibited increased expression of inhibitory receptors including PD1, Tim3 and LAG3 and were dysfunctional following adoptive transfer in a model of TCR-dependent leukemia clearance. Although expression of inhibitory receptors has been linked to TCR signaling, pre-B ALL induced inhibitory receptor expression, at least in part, via a T cell receptor (TCR) independent manner. Finally, introduction of a CAR into T cells generated from leukemia-bearing mice failed to fully reverse poor in vivo function.

Author Info: (1) Hematologic Malignancies Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States. (2) Hematologic Malignancies Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States. (3) Hematologic Malignancies Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States. (4) Howard Hughes Medical Institute, Chevy Chase, MD, United States. (5) Hematologic Malignancies Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States. (6) CCBR Bioinformatics, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD, United States. (7) Hematologic Malignancies Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States. (8) Hematologic Malignancies Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States. (9) Hematologic Malignancies Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States. (10) Hematologic Malignancies Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States. (11) Hematologic Malignancies Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States; terry.fry@ucdenver.edu.

Citation: Blood 2018 Sep 12 Epub09/12/2018

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/30209120

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Antibody-Neutralized Reovirus Is Effective in Oncolytic Virotherapy

(1) Berkeley RA (2) Steele LP (3) Mulder AA (4) van den Wollenberg DJM (5) Kottke TJ (6) Thompson J (7) Coffey M (8) Hoeben RC (9) Vile RG (10) Melcher A (11) Ilett EJ

(1) Berkeley RA (2) Steele LP (3) Mulder AA (4) van den Wollenberg DJM (5) Kottke TJ (6) Thompson J (7) Coffey M (8) Hoeben RC (9) Vile RG (10) Melcher A (11) Ilett EJ

Immunotherapy is showing promise for otherwise incurable cancers. Oncolytic viruses (OVs), developed as direct cytotoxic agents, mediate their antitumor effects via activation of the immune system. However, OVs also stimulate antiviral immune responses, including the induction of OV-neutralizing antibodies. Current dogma suggests that the presence of preexisting antiviral neutralizing antibodies in patients, or their development during viral therapy, is a barrier to systemic OV delivery, rendering repeat systemic treatments ineffective. However, we have found that human monocytes loaded with preformed reovirus-antibody complexes, in which the reovirus is fully neutralized, deliver functional replicative reovirus to tumor cells, resulting in tumor cell infection and lysis. This delivery mechanism is mediated, at least in part, by antibody receptors (in particular FcgammaRIII) that mediate uptake and internalization of the reovirus/antibody complexes by the monocytes. This finding has implications for oncolytic virotherapy and for the design of clinical OV treatment strategies. Cancer Immunol Res; 1-13. (c)2018 AACR.

Author Info: (1) Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom. (2) Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United

Author Info: (1) Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom. (2) Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom. (3) Leiden University Medical Centre, Department of Molecular Cell Biology, Leiden, the Netherlands. (4) Leiden University Medical Centre, Department of Molecular Cell Biology, Leiden, the Netherlands. (5) Department of Immunology, Mayo Clinic, Rochester, Minnesota. (6) Department of Immunology, Mayo Clinic, Rochester, Minnesota. (7) Oncolytics Biotech Incorporated, Calgary, Alberta, Canada. (8) Leiden University Medical Centre, Department of Molecular Cell Biology, Leiden, the Netherlands. (9) Department of Immunology, Mayo Clinic, Rochester, Minnesota. (10) Institute of Cancer Research, London, United Kingdom. (11) Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom. e.ilett@leeds.ac.uk.

Citation: Cancer Immunol Res 2018 Sep 12 Epub09/12/2018

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/30209061

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CAR-T Cells Based on Novel BCMA Monoclonal Antibody Block Multiple Myeloma Cell Growth

(1) Berahovich R (2) Zhou H (3) Xu S (4) Wei Y (5) Guan J (6) Guan J (7) Harto H (8) Fu S (9) Yang K (10) Zhu S (11) Li L (12) Wu L (13) Golubovskaya V

Cancers

(1) Berahovich R (2) Zhou H (3) Xu S (4) Wei Y (5) Guan J (6) Guan J (7) Harto H (8) Fu S (9) Yang K (10) Zhu S (11) Li L (12) Wu L (13) Golubovskaya V

Cancers

The cell-surface protein B cell maturation antigen (BCMA, CD269) has emerged as a promising target for CAR-T cell therapy for multiple myeloma. In order to create a novel BCMA CAR, we generated a new BCMA monoclonal antibody, clone 4C8A. This antibody exhibited strong and selective binding to human BCMA. BCMA CAR-T cells containing the 4C8A scFv were readily detected with recombinant BCMA protein by flow cytometry. The cells were cytolytic for RPMI8226, H929, and MM1S multiple myeloma cells and secreted high levels of IFN-gamma in vitro. BCMA-dependent cytotoxicity and IFN-gamma secretion were also observed in response to CHO (Chinese Hamster Ovary)-BCMA cells but not to parental CHO cells. In a mouse subcutaneous tumor model, BCMA CAR-T cells significantly blocked RPMI8226 tumor formation. When BCMA CAR-T cells were given to mice with established RPMI8226 tumors, the tumors experienced significant shrinkage due to CAR-T cell activity and tumor cell apoptosis. The same effect was observed with 3 humanized BCMA-CAR-T cells in vivo. These data indicate that novel CAR-T cells utilizing the BCMA 4C8A scFv are effective against multiple myeloma and warrant future clinical development.

Author Info: (1) ProMab Biotechnologies, 2600 Hilltop Drive, Richmond, CA 94806, USA. robert.berahovich@promab.com. (2) ProMab Biotechnologies, 2600 Hilltop Drive, Richmond, CA 94806, USA. huazhou369@gmail.com. (3) ProMab Biotechnologies, 2600 Hilltop Drive, Richmond, CA 94806, USA. shirley.xu@promab.com. (4) ProMab Biotechnologies, 2600 Hilltop Drive, Richmond, CA 94806, USA. yuehua.wei@promab.com. (5) ProMab Biotechnologies, 2600 Hilltop Drive, Richmond, CA 94806, USA. jasper.guan@promab.com. (6) ProMab Biotechnologies, 2600 Hilltop Drive, Richmond, CA 94806, USA. jian.guan@promab.com. (7) ProMab Biotechnologies, 2600 Hilltop Drive, Richmond, CA 94806, USA. hizkia.harto@promab.com. (8) Forevertek Biotechnology Co., Ltd., Building M0, Oversea Graduate Park National High-Tech Industrial Zone, Changsha 410003, China. promab8807@126.com. (9) Forevertek Biotechnology Co., Ltd., Building M0, Oversea Graduate Park National High-Tech Industrial Zone, Changsha 410003, China. yangkaihuai520@126.com. (10) Forevertek Biotechnology Co., Ltd., Building M0, Oversea Graduate Park National High-Tech Industrial Zone, Changsha 410003, China. shuying256@163.com. (11) ProMab Biotechnologies, 2600 Hilltop Drive, Richmond, CA 94806, USA. simon.li@promab.com. Forevertek Biotechnology Co., Ltd., Building M0, Oversea Graduate Park National High-Tech Industrial Zone, Changsha 410003, China. simon.li@promab.com. (12) ProMab Biotechnologies, 2600 Hilltop Drive, Richmond, CA 94806, USA. john@promab.com. (13) ProMab Biotechnologies, 2600 Hilltop Drive, Richmond, CA 94806, USA. vita.gol@promab.com.

Citation: Cancers (Basel) 2018 Sep 11 10: Epub09/11/2018

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/30208593

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Cancer immunology, immunotherapy

A phase I/randomized phase II study of GM.CD40L vaccine in combination with CCL21 in patients with advanced lung adenocarcinoma

(1) Gray JE (2) Chiappori A (3) Williams CC (4) Tanvetyanon T (5) Haura EB (6) Creelan BC (7) Kim J (8) Boyle TA (9) Pinder-Schenck M (10) Khalil F (11) Altiok S (12) Devane R (13) Noyes D (14) Mediavilla-Varela M (15) Smilee R (16) Hopewell EL (17) Kelley L (18) Antonia SJ

The GM.CD40L vaccine, which recruits and activates dendritic cells, migrates to lymph nodes, activating T cells and leading to systemic tumor cell killing. When combined with the CCL21 chemokine, which recruits T cells and enhances T-cell responses, additive effects have been demonstrated in non-small cell lung cancer mouse models. Here, we compared GM.CD40L versus GM.CD40L plus CCL21 (GM.CD40L.CCL21) in lung adenocarcinoma patients with >/= 1 line of treatment. In this phase I/II randomized trial (NCT01433172), patients received intradermal vaccines every 14 days (3 doses) and then monthly (3 doses). A two-stage minimax design was used. During phase I, no dose-limiting toxicities were shown in three patients who received GM.CD40L.CCL21. During phase II, of evaluable patients, 5/33 patients (15.2%) randomized for GM.DCD40L (p = .023) and 3/32 patients (9.4%) randomized for GM.DCD40L.CCL21 (p = .20) showed 6-month progression-free survival. Median overall survival was 9.3 versus 9.5 months with GM.DCD40L versus GM.DCD40L.CCL21 (95% CI 0.70-2.25; p = .44). For GM.CD40L versus GM.CD40L.CCL21, the most common treatment-related adverse events (TRAEs) were grade 1/2 injection site reaction (51.4% versus 61.1%) and grade 1/2 fatigue (35.1% versus 47.2%). Grade 1 immune-mediated TRAEs were isolated to skin. No patients showed evidence of pseudo-progression or immune-related TRAEs of grade 1 or greater of pneumonitis, endocrinopathy, or colitis, and none discontinued treatment due to toxicity. Although we found no significant associations between vaccine immunogenicity and outcomes, in limited biopsies, one patient treated with GMCD40L.CCL21 displayed abundant tumor-infiltrating lymphocytes. This possible effectiveness warrants further investigation of GM.CD40L in combination approaches.

Author Info: (1) Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, FOB1, Tampa, FL, 33612, USA. Jhanelle.gray@moffitt.org. (2) Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, FOB1, Tampa, FL, 33612, USA. (3) Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, FOB1, Tampa, FL, 33612, USA. (4) Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, FOB1, Tampa, FL, 33612, USA. (5) Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, FOB1, Tampa, FL, 33612, USA. (6) Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, FOB1, Tampa, FL, 33612, USA. (7) Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. (8) Department of Anatomic Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. (9) GlaxoSmithKline, Collegeville, PA, USA. (10) Department of Anatomic Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. (11) Department of Anatomic Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. (12) Clinical Trials Office, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. (13) Clinical Science Lab (Antonia Lab), H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. (14) Clinical Science Lab (Antonia Lab), H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. (15) Cell Therapy Core, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. (16) Cell Therapy Core, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. (17) Cell Therapy Core, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. (18) Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, FOB1, Tampa, FL, 33612, USA.

Citation: Cancer Immunol Immunother 2018 Sep 12 Epub09/12/2018

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/30209589

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Stromal Fibroblasts Mediate Anti-PD-1 Resistance via MMP-9 and Dictate TGF-beta Inhibitor Sequencing in Melanoma

(1) Zhao F (2) Evans KS (3) Xiao C (4) DeVito N (5) Theivanthiran B (6) Holtzhausen A (7) Siska PJ (8) Blobe GC (9) Hanks BA

(1) Zhao F (2) Evans KS (3) Xiao C (4) DeVito N (5) Theivanthiran B (6) Holtzhausen A (7) Siska PJ (8) Blobe GC (9) Hanks BA

Although anti-PD-1 therapy has improved clinical outcomes for select patients with advanced cancer, many patients exhibit either primary or adaptive resistance to checkpoint inhibitor immunotherapy. The role of the tumor stroma in the development of these mechanisms of resistance to checkpoint inhibitors remains unclear. We demonstrated that pharmacological inhibition of the TGF-beta signaling pathway synergistically enhanced the efficacy of anti-CTLA-4 immunotherapy but failed to augment anti-PD-1/PD-L1 responses in an autochthonous model of BRAF(V600E) melanoma. Additional mechanistic studies revealed that TGF-beta pathway inhibition promoted the proliferative expansion of stromal fibroblasts, thereby, facilitating MMP-9-dependent cleavage of PD-L1 surface expression, leading to anti-PD-1 resistance in this model. Further work demonstrated that melanomas escaping anti-PD-1 therapy exhibited a mesenchymal phenotype associated with enhanced TGF-beta signaling activity. Delayed TGF-beta inhibitor therapy, following anti-PD-1 escape, better served to control further disease progression and was superior to a continuous combination of anti-PD-1 and TGF-beta inhibition. This work illustrates that formulating immunotherapy combination regimens to enhance the efficacy of checkpoint blockade requires an in-depth understanding of the impact of these agents on the tumor microenvironment. These data indicated that stromal fibroblast MMP-9 may desensitize tumors to anti-PD-1 and suggests that TGF-beta inhibition may generate greater immunologic efficacy when administered following the development of acquired anti-PD-1 resistance.

Author Info: (1) NIEHS/IIDL, NIH. (2) Internal Medicine/Medical Oncology, Duke University Medical Center. (3) Internal Medicine/Medical Oncology, Duke University Medical Center. (4) Medicine, Duke University Medical Center. (5) Internal Medicine/Medical Oncology, Duke University Medical Center. (6) Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill. (7) Internal Medicine III, University Hospital Regensburg. (8) Pharmacology & Cancer Biology, Duke University Medical Center. (9) Internal Medicine/Medical Oncology and Pharmacology/Cancer Biology, Duke University Medical Center hanks004@mc.duke.edu.

Citation: Cancer Immunol Res 2018 Sep 12 Epub09/12/2018

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/30209062

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Seminars in immunopathology

Extracellular vesicles in cancer immune responses: roles of purinergic receptors

(1) Graner MW

(1) Graner MW

Seminars in immunopathology

Extracellular vesicles (EVs) are nano- to micro-scale membrane-enclosed vesicles that are released from presumably all cell types. Tumor cells and immune cells are prodigious generators of EVs often with competing phenotypes in terms of immune suppression versus immune stimulation. Purinergic receptors, proteins that bind diverse purine nucleotides and nucleosides (ATP, ADP, AMP, adenosine), are widely expressed across tissues and cell types, and are prominent players in immune and tumor cell nucleotide metabolism. The effects of purinergic receptor stimulation or agonism tend to produce inflammatory responses that may aid immune stimulation but may also provoke various immune suppression mechanisms, particularly in the tumor microenvironment. EVs released by cells following receptor stimulation are frequently pro-inflammatory, but often also pro-thrombolytic; these EVs may generate an environment that favors tumor progression at the cost of an effective immune response. Purinergic signaling pathways are becoming more recognized as valuable targets in various therapeutic scenarios, including cancer. It is possible that some of those clinically relevant compounds might also impact EV secretion and/or phenotype, which would hopefully capitalize on the immune stimulatory properties of purinergic signaling while minimizing the immune suppressive consequences. This review covers a relatively understudied area in EV biology, but even so, focuses almost exclusively on the purinergic receptors in a very limited capacity. There is much more to evaluate and incorporate into our understanding of extracellular nucleotides in EV biology, and we hope this work prompts further discovery.

Author Info: (1) Department of Neurosurgery, University of Colorado Denver, Anschutz Medical Campus, RC2, 12700 E 19th Ave, Room 5125, Aurora, CO, 80045, USA. michael.graner@ucdenver.edu.

Citation: Semin Immunopathol 2018 Sep 12 Epub09/12/2018

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/30209547

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