ABSTRACT
The acidic tumor microenvironment in melanoma drives immune evasion by up-regulating cyclic adenosine monophosphate (cAMP) in tumor-infiltrating monocytes. Here we show that the release of non-toxic concentrations of an adenylate cyclase (AC) inhibitor from poly(sarcosine)-block-poly(L-glutamic acid γ-benzyl ester) (polypept(o)id) copolymer micelles restores antitumor immunity. In combination with selective, non-therapeutic regulatory T cell depletion, AC inhibitor micelles achieve a complete remission of established B16-F10-OVA tumors. Single-cell sequencing of melanoma-infiltrating immune cells shows that AC inhibitor micelles reduce the number of anti-inflammatory myeloid cells and checkpoint receptor expression on T cells. AC inhibitor micelles thus represent an immunotherapeutic measure to counteract melanoma immune escape.
Subject(s)
Adenylyl Cyclase Inhibitors/pharmacology , Adenylyl Cyclases/genetics , Antineoplastic Agents/pharmacology , Cyclic AMP/antagonists & inhibitors , Melanoma, Experimental/drug therapy , Skin Neoplasms/drug therapy , Adenylyl Cyclase Inhibitors/chemical synthesis , Adenylyl Cyclases/immunology , Animals , Antineoplastic Agents/chemical synthesis , Benzyl Compounds/chemistry , Cyclic AMP/immunology , Cyclic AMP/metabolism , Esters , Female , Gene Expression , Humans , Immunity, Innate/drug effects , Injections, Intralesional , Interleukin 1 Receptor Antagonist Protein/genetics , Interleukin 1 Receptor Antagonist Protein/immunology , Melanoma, Experimental/genetics , Melanoma, Experimental/immunology , Melanoma, Experimental/pathology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Micelles , Myeloid Cells/drug effects , Myeloid Cells/immunology , Myeloid Cells/pathology , Peptides/chemistry , Polyglutamic Acid/chemistry , Receptors, Immunologic/antagonists & inhibitors , Receptors, Immunologic/genetics , Receptors, Immunologic/immunology , Sarcosine/analogs & derivatives , Sarcosine/chemistry , Skin Neoplasms/genetics , Skin Neoplasms/immunology , Skin Neoplasms/pathology , T-Lymphocytes, Regulatory/drug effects , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/pathology , Tumor Burden/drug effects , Tumor Escape/drug effects , Tumor Microenvironment/drug effects , Tumor Microenvironment/genetics , Tumor Microenvironment/immunologyABSTRACT
Many tumors evolve sophisticated strategies to evade the immune system, and these represent major obstacles for efficient antitumor immune responses. Here we explored a molecular mechanism of metabolic communication deployed by highly glycolytic tumors for immunoevasion. In contrast to colon adenocarcinomas, melanomas showed comparatively high glycolytic activity, which resulted in high acidification of the tumor microenvironment. This tumor acidosis induced Gprotein-coupled receptor-dependent expression of the transcriptional repressor ICER in tumor-associated macrophages that led to their functional polarization toward a non-inflammatory phenotype and promoted tumor growth. Collectively, our findings identify a molecular mechanism of metabolic communication between non-lymphoid tissue and the immune system that was exploited by high-glycolytic-rate tumors for evasion of the immune system.
Subject(s)
Adenocarcinoma/immunology , Macrophages/immunology , Melanoma/immunology , Tumor Escape/immunology , Tumor Microenvironment/immunology , Acidosis/immunology , Adenocarcinoma/metabolism , Animals , Colonic Neoplasms/immunology , Colonic Neoplasms/metabolism , Glycolysis/immunology , Humans , Melanoma/metabolism , Mice , Mice, Inbred C57BL , Mice, TransgenicABSTRACT
RATIONALE: Immune cells play an important role during the generation and resolution of thrombosis. T cells are powerful regulators of immune and nonimmune cell function, however, their role in sterile inflammation in venous thrombosis has not been systematically examined. OBJECTIVE: This study investigated the recruitment, activation, and inflammatory activity of T cells in deep vein thrombosis and its consequences for venous thrombus resolution. METHODS AND RESULTS: CD4+ and CD8+ T cells infiltrate the thrombus and vein wall rapidly on deep vein thrombosis induction and remain in the tissue throughout the thrombus resolution. In the vein wall, recruited T cells largely consist of effector-memory T (TEM) cells. Using T-cell receptor transgenic reporter mice, we demonstrate that deep vein thrombosis-recruited TEM receive an immediate antigen-independent activation and produce IFN-γ (interferon) in situ. Mapping inflammatory conditions in the thrombotic vein, we identify a set of deep vein thrombosis upregulated cytokines and chemokines that synergize to induce antigen-independent IFN-γ production in CD4+ and CD8+ TEM cells. Reducing the number of TEM cells through a depletion recovery procedure, we show that intravenous TEM activation determines neutrophil and monocyte recruitment and delays thrombus neovascularization and resolution. Examining T-cell recruitment in human venous stasis, we show that superficial varicose veins preferentially contain activated memory T cells. CONCLUSIONS: TEM orchestrate the inflammatory response in venous thrombosis affecting thrombus resolution.
Subject(s)
CD4-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/metabolism , Immunity, Innate/physiology , Varicose Veins/metabolism , Venous Thrombosis/metabolism , Animals , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Humans , Inflammation/immunology , Inflammation/metabolism , Mice , Mice, 129 Strain , Mice, Inbred C57BL , Mice, Transgenic , Thrombosis/immunology , Thrombosis/metabolism , Varicose Veins/immunology , Venous Thrombosis/immunologyABSTRACT
Viruses represent an important cause of cancer in humans: infections are estimated to account for close to one cancer case out of five.With the ongoing discovery of new infectious agents, this number should be raising in the near future. In 2006, the discovery of a new _-retrovirus in prostate cancer biopsies launched an intense research activity: could this new xenotropic MLV-related virus (XMRV) be the cause of prostate cancer? Five years later, the initial enthusiasm of retrovirologists has dramatically diminished. One by one, arguments favouring the hypothesis of human infection with XMRV are being refuted. The aim of this review article is to present the discovery of XMRV and to analyze recent data arguing against its existence in humans. A synthetic interpretation of XMRV literature will then be suggested.
