Dataset Information

Tumor-Derived IL33 Promotes Tissue-Resident CD8⁺ T Cells and Is Required for Checkpoint Blockade Tumor Immunotherapy.

ABSTRACT: 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.

SUBMITTER: Chen L

PROVIDER: S-EPMC7642190 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Tumor-Derived IL33 Promotes Tissue-Resident CD8<sup>+</sup> T Cells and Is Required for Checkpoint Blockade Tumor Immunotherapy.

Chen Lujun L Sun Runzi R Xu Junchi J Zhai Wensi W Zhang Dachuan D Yang Min M Yue Cuihua C Chen Yichao Y Li Song S Turnquist Heth H Jiang Jingting J Lu Binfeng B

Cancer immunology research 20200911 11

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 antige ...[more]

PMID: 32917659

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Project description:BackgroundPersonalized neoantigen vaccine could induce a robust antitumor immune response in multiple cancers, whose efficacy could be further enhanced by combining with programmed cell death 1 blockade (α-PD-1). However, the corresponding immune response and synergistic mechanisms remain largely unclear. Here, we aimed to develop clinically available combinational therapeutic strategy and further explore its potential antitumor mechanisms in hepatocellular carcinoma (HCC).MethodsNeoantigen peptide vaccine (NeoVAC) for murine HCC cell line Hepa1-6 was developed and optimized by neoantigen screening and adjuvant optimization. Then the synergistic efficacy and related molecular mechanisms of NeoVAC combined with α-PD-1 in HCC were evaluated by orthotopic HCC mouse model, single-cell RNA sequencing, tetramer flow cytometry, immunofluorescence, etc. The tumor-killing capacity of CD8+ tissue-resident memory T cells (CD8+ TRMs) was assessed by orthotopic HCC mouse model, and autologous patient-derived cells.ResultsNeoVAC, which consisted of seven high immunogenic neoantigen peptides and clinical-grade Poly(I:C), could generate a strong antitumor immune response in HCC mouse models. Significantly, its efficacy could be further improved by combining with α-PD-1, with 80% of durable tumor regression and long-term immune memory in orthotopic HCC models. Moreover, in-depth analysis of the tumor immune microenvironment showed that the percentage of CD8+ TRMs was remarkedly increased in NeoVAC plus α-PD-1 treatment group, and positively associated with the antitumor efficacy. In vitro and in vivo T-cell cytotoxicity assay further confirmed the strong tumor-killing capacity of CD8+ TRMs sorting from orthotopic mouse HCC or patient's HCC tissue.ConclusionsThis study showed that NeoVAC plus α-PD-1 could induce a strong antitumor response and long-term tumor-specific immune memory in HCC by increasing CD8+ TRMs infiltration, which might serve as a potential immune-therapeutic target for HCC.

Dataset Information

Tumor-Derived IL33 Promotes Tissue-Resident CD8⁺ T Cells and Is Required for Checkpoint Blockade Tumor Immunotherapy.

Publications

Tumor-Derived IL33 Promotes Tissue-Resident CD8<sup>+</sup> T Cells and Is Required for Checkpoint Blockade Tumor Immunotherapy.

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Dataset Information

Tumor-Derived IL33 Promotes Tissue-Resident CD8+ T Cells and Is Required for Checkpoint Blockade Tumor Immunotherapy.

Publications

Tumor-Derived IL33 Promotes Tissue-Resident CD8<sup>+</sup> T Cells and Is Required for Checkpoint Blockade Tumor Immunotherapy.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Tumor-Derived IL33 Promotes Tissue-Resident CD8⁺ T Cells and Is Required for Checkpoint Blockade Tumor Immunotherapy.