Tumor-derived IL33 Promotes tissue-resident CD8^þ T cells and is required for checkpoint blockade tumor immunotherapy

TY - JOUR

T1 - Tumor-derived IL33 Promotes tissue-resident CD8þ T cells and is required for checkpoint blockade tumor immunotherapy

AU - Chen, Lujun

AU - Sun, Runzi

AU - Xu, Junchi

AU - Zhai, Wensi

AU - Zhang, Dachuan

AU - Yang, Min

AU - Yue, Cuihua

AU - Chen, Yichao

AU - Li, Song

AU - Turnquist, Heth

AU - Jiang, Jingting

AU - Lu, Binfeng

N1 - Publisher Copyright: © 2020 American Association for Cancer Research.

PY - 2020/11/1

Y1 - 2020/11/1

N2 - 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 CD8þ 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 CD103þCD8þ T cells, and CD103 expression on CD8þ T cells was required for the antitumor efficacy of IL33. In addition, IL33 also increased the numbers of CD103þ dendritic cells (DC) in the TME and CD103þ DC were required for the antitumor effect of IL33 and accumulation of tumor-infiltrating CD8þ 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.

AB - 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 CD8þ 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 CD103þCD8þ T cells, and CD103 expression on CD8þ T cells was required for the antitumor efficacy of IL33. In addition, IL33 also increased the numbers of CD103þ dendritic cells (DC) in the TME and CD103þ DC were required for the antitumor effect of IL33 and accumulation of tumor-infiltrating CD8þ 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.

UR - https://www.scopus.com/pages/publications/85096782138

U2 - 10.1158/2326-6066.CIR-19-1024

DO - 10.1158/2326-6066.CIR-19-1024

M3 - Article

C2 - 32917659

SN - 2326-6066

VL - 8

SP - 1381

EP - 1392

JO - Cancer immunology research

JF - Cancer immunology research

IS - 11

ER -