ABSTRACT
IL1ß is a central mediator of inflammation. Secretion of IL1ß typically requires proteolytic maturation by the inflammasome and formation of membrane pores by gasdermin D (GSDMD). Emerging evidence suggests an important role for IL1ß in promoting cancer progression in patients, but the underlying mechanisms are ill-defined. Here, we have shown a key role for IL1ß in driving tumor progression in two distinct mouse tumor models. Notably, activation of the inflammasome, caspase-8, as well as the pore-forming proteins GSDMD and mixed lineage kinase domain-like protein in the host were dispensable for the release of intratumoral bioactive IL1ß. Inflammasome-independent IL1ß release promoted systemic neutrophil expansion and fostered accumulation of T-cell-suppressive neutrophils in the tumor. Moreover, IL1ß was essential for neutrophil infiltration triggered by antiangiogenic therapy, thereby contributing to treatment-induced immunosuppression. Deletion of IL1ß allowed intratumoral accumulation of CD8+ effector T cells that subsequently activated tumor-associated macrophages. Depletion of either CD8+ T cells or macrophages abolished tumor growth inhibition in IL1ß-deficient mice, demonstrating a crucial role for CD8+ T-cell-macrophage cross-talk in the antitumor immune response. Overall, these results support a tumor-promoting role for IL1ß through establishing an immunosuppressive microenvironment and show that inflammasome activation is not essential for release of this cytokine in tumors.
Subject(s)
Interleukin-1beta/metabolism , Neoplasms/immunology , Neutrophils/immunology , Tumor Escape , Tumor Microenvironment/immunology , Animals , Cell Communication/immunology , Disease Models, Animal , Female , Humans , Inflammasomes/immunology , Inflammasomes/metabolism , Interleukin-1beta/genetics , Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/metabolism , Lymphocytes, Tumor-Infiltrating/immunology , Mice , Mice, Knockout , Neoplasms/pathology , Neutrophils/metabolism , Phosphate-Binding Proteins/genetics , Phosphate-Binding Proteins/metabolism , T-Lymphocytes, Cytotoxic/immunology , Tumor-Associated Macrophages/immunologyABSTRACT
Cancer immunotherapy aims to augment the response of the patient's own immune system against cancer cells. Despite effective for some patients and some cancer types, the therapeutic efficacy of this treatment is limited by the composition of the tumor microenvironment (TME), which is not well-suited for the fitness of anti-tumoral immune cells. However, the TME differs between cancer types and tissues, thus complicating the possibility of the development of therapies that would be effective in a large range of patients. A possible scenario is that each type of cancer cell, granted by its own mutations and reminiscent of the functions of the tissue of origin, has a specific metabolism that will impinge on the metabolic composition of the TME, which in turn specifically affects T cell fitness. Therefore, targeting cancer or T cell metabolism could increase the efficacy and specificity of existing immunotherapies, improving disease outcome and minimizing adverse reactions.
Subject(s)
Immunotherapy , Neoplasms , Humans , Immunity , Neoplasms/therapy , T-Lymphocytes , Tumor MicroenvironmentABSTRACT
Among mammary tumor-infiltrating immune cells, the highest expression of podoplanin (PDPN) is found in a subset of tumor-associated macrophages (TAMs). We hereby demonstrate that PDPN is involved in the attachment of this TAM subset to lymphatic endothelial cells (LECs). Mechanistically, the binding of PDPN to LEC-derived galectin 8 (GAL8) in a glycosylation-dependent manner promotes the activation of pro-migratory integrin ß1. When proximal to lymphatics, PDPN-expressing macrophages (PoEMs) stimulate local matrix remodeling and promote vessel growth and lymphoinvasion. Anti-integrin ß1 blockade, macrophage-specific Pdpn knockout, or GAL8 inhibition impairs TAM adhesion to LECs, restraining lymphangiogenesis and reducing lymphatic cancer spread. In breast cancer patients, association of PoEMs with tumor lymphatic vessels correlates with incidences of lymph node and distant organ metastasis.
Subject(s)
Breast Neoplasms/metabolism , Lymph Nodes/pathology , Lymphangiogenesis/genetics , Lymphatic Metastasis/genetics , Macrophages/metabolism , Membrane Glycoproteins/metabolism , Adult , Aged , Aged, 80 and over , Animals , Breast Neoplasms/pathology , Cell Line, Tumor , Endothelial Cells/metabolism , Extracellular Matrix/metabolism , Female , Humans , Lymphatic Vessels/metabolism , Membrane Glycoproteins/genetics , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Middle AgedABSTRACT
TLR3 belong to the Toll-like receptors family, it is mainly expressed on immune cells where it senses pathogen-associated molecular patterns and initiates innate immune response. TLR3 agonist poly(I:C) was developed to mimic pathogens infection and boost immune system activation to promote anti-cancer therapy. Accordingly, TLR agonists were included in the National Cancer Institute list of immunotherapeutic agents with the highest potential to cure cancer. Besides well known effects on immune cells, poly(I:C) was also shown, in experimental models, to directly induce apoptosis in cancer cells expressing TLR3. This review presents the current knowledge on the mechanism of poly(I:C)-induced apoptosis in cancer cells. Experimental evidences on positive or negative regulators of TLR3-mediated apoptosis induced by poly(I:C) are reported and strategies are proposed to successfully promote this event in cancer cells. Cancer cells apoptosis is an additional arm offered by poly(I:C), besides activation of immune system, for the treatment of various type of cancer. A further dissection of TLR3 signaling would contribute to greater resolution of the critical steps that impede full exploitation of the poly(I:C)-induced apoptosis. Experimental evidences about negative regulator of poly(I:C)-induced apoptotic program should be considered in combinations with TLR3 agonists in clinical trials.
