ABSTRACT
Antibiotics (ABX) compromise the efficacy of programmed cell death protein 1 (PD-1) blockade in cancer patients, but the mechanisms underlying their immunosuppressive effects remain unknown. By inducing the down-regulation of mucosal addressin cell adhesion molecule 1 (MAdCAM-1) in the ileum, post-ABX gut recolonization by Enterocloster species drove the emigration of enterotropic α4ß7+CD4+ regulatory T 17 cells into the tumor. These deleterious ABX effects were mimicked by oral gavage of Enterocloster species, by genetic deficiency, or by antibody-mediated neutralization of MAdCAM-1 and its receptor, α4ß7 integrin. By contrast, fecal microbiota transplantation or interleukin-17A neutralization prevented ABX-induced immunosuppression. In independent lung, kidney, and bladder cancer patient cohorts, low serum levels of soluble MAdCAM-1 had a negative prognostic impact. Thus, the MAdCAM-1-α4ß7 axis constitutes an actionable gut immune checkpoint in cancer immunosurveillance.
Subject(s)
Anti-Bacterial Agents , Cell Adhesion Molecules , Drug Resistance, Neoplasm , Gastrointestinal Microbiome , Immune Checkpoint Inhibitors , Immune Tolerance , Immunologic Surveillance , Integrins , Mucoproteins , Neoplasms , Animals , Humans , Mice , Anti-Bacterial Agents/adverse effects , Bacteria/immunology , Cell Adhesion Molecules/metabolism , Cell Movement , Fecal Microbiota Transplantation , Gastrointestinal Microbiome/immunology , Immune Checkpoint Inhibitors/therapeutic use , Immune Tolerance/drug effects , Integrins/metabolism , Interleukin-17/metabolism , Mucoproteins/metabolism , Neoplasms/immunology , Neoplasms/therapy , Th17 Cells/immunology , Gastrointestinal Tract/immunology , Gastrointestinal Tract/microbiologyABSTRACT
Although T cells can exert potent anti-tumor immunity, a subset of T helper (Th) cells producing interleukin-22 (IL-22) in breast and lung tumors is linked to dismal patient outcome. Here, we examined the mechanisms whereby these T cells contribute to disease. In murine models of lung and breast cancer, constitutional and T cell-specific deletion of Il22 reduced metastases without affecting primary tumor growth. Deletion of the IL-22 receptor on cancer cells decreases metastasis to a degree similar to that seen in IL-22-deficient mice. IL-22 induced high expression of CD155, which bound to the activating receptor CD226 on NK cells. Excessive activation led to decreased amounts of CD226 and functionally impaired NK cells, which elevated the metastatic burden. IL-22 signaling was also associated with CD155 expression in human datasets and with poor patient outcomes. Taken together, our findings reveal an immunosuppressive circuit activated by T cell-derived IL-22 that promotes lung metastasis.
Subject(s)
Interleukins , Neoplasms , Receptors, Virus , T-Lymphocytes, Helper-Inducer , Animals , Humans , Mice , Antigens, Differentiation, T-Lymphocyte/metabolism , Interleukins/genetics , Interleukins/metabolism , Killer Cells, Natural/metabolism , Neoplasms/metabolism , Protein Binding , T-Lymphocytes, Helper-Inducer/metabolism , Interleukin-22ABSTRACT
CAR T cell therapy remains ineffective in solid tumors, due largely to poor infiltration and T cell suppression at the tumor site. T regulatory (Treg) cells suppress the immune response via inhibitory factors such as transforming growth factor-ß (TGF-ß). Treg cells expressing the C-C chemokine receptor 8 (CCR8) have been associated with poor prognosis in solid tumors. We postulated that CCR8 could be exploited to redirect effector T cells to the tumor site while a dominant-negative TGF-ß receptor 2 (DNR) can simultaneously shield them from TGF-ß. We identified that CCL1 from activated T cells potentiates a feedback loop for CCR8+ T cell recruitment to the tumor site. This sustained and improved infiltration of engineered T cells synergized with TGF-ß shielding for improved therapeutic efficacy. Our results demonstrate that addition of CCR8 and DNR into CAR T cells can render them effective in solid tumors.