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Immune checkpoint blockade (ICB) immunotherapy has revolutionized cancer treatment by prolonging overall survival of patients with cancer. Despite advances in the clinical setting, the immune cellular network in the tumor microenvironment (TME) that mediates such therapy is not well understood. IL33 is highly expressed in normal epithelial cells but downregulated in tumor cells in advanced carcinoma. Here, we showed that IL33 was induced in tumor cells after treatment with ICB such as CTL antigen-4 (CTLA-4) and programmed death-1 (PD-1) mAbs. ST2 signaling in nontumor cells, particularly CD8 + T cells, was critical for the antitumor efficacy of ICB immunotherapy. We demonstrated that tumor-derived IL33 was crucial for the antitumor efficacy of checkpoint inhibitors. Mechanistically, IL33 increased the accumulation and effector function of tumor-resident CD103 + CD8 + T cells, and CD103 expression on CD8 + T cells was required for the antitumor efficacy of IL33. In addition, IL33 also increased the numbers of CD103 + dendritic cells (DC) in the TME and CD103 + DC were required for the antitumor effect of IL33 and accumulation of tumor-infiltrating CD8 + T cells. Combination of IL33 with CTLA-4 and PD-1 ICB further prolonged survival of tumor-bearing mice. Our study established that the "danger signal" IL33 was crucial for mediating ICB cancer therapy by promoting tumor-resident adaptive immune responses., (©2020 American Association for Cancer Research.)

T cells are strongly regulated by oxidizing environments and amino acid restriction. How T cells reprogram metabolism to adapt to these extracellular stress situations is not well understood. Here, we show that oxidizing environments and amino acid starvation induce ATF4 in CD4 + T cells. We also demonstrate that Atf4-deficient CD4 + T cells have defects in redox homeostasis, proliferation, differentiation, and cytokine production. We further reveal that ATF4 regulates a coordinated gene network that drives amino acid intake, mTORC1 activation, protein translation, and an anabolic program for de novo synthesis of amino acids and glutathione. ATF4 also promotes catabolic glycolysis and glutaminolysis and oxidative phosphorylation and thereby provides precursors and energy for anabolic pathways. ATF4-deficient mice mount reduced Th1 but elevated Th17 immune responses and develop more severe experimental allergic encephalomyelitis (EAE). Our study demonstrates that ATF4 is critical for CD4 + T cell-mediated immune responses through driving metabolic adaptation., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)