TIM-3 blockade enhances IL-12-dependent antitumor immunity by promoting CD8+ T cell and XCR1+ dendritic cell spatial co-localization. Issue 1 (5th January 2022)

• Record Type: Journal Article
• Authors: Gardner, Alycia; de Mingo Pulido, Álvaro; Hänggi, Kay; Bazargan, Sarah; Onimus, Alexis; Kasprzak, Agnieszka; Conejo-Garcia, Jose R; Rejniak, Katarzyna A; Ruffell, Brian
• Is Part Of: Journal for immunotherapy of cancer. Volume 10:Issue 1(2022)
• Publication Date: 2022-01-05
• Subjects: dendritic cells -- breast neoplasms -- CD8-positive T-lymphocytes -- costimulatory and inhibitory T-cell receptors -- tumor microenvironment; Cancer -- Immunotherapy -- Periodicals; Cancer -- Immunological aspects -- Periodicals; Tumors -- Immunological aspects -- Periodicals; Immunotherapy -- Periodicals; 616.99406105
• DOI: 10.1136/jitc-2021-003571
• Languages: English
• ISSNs: 2051-1426

Abstract

Abstract : Background: T cell immunoglobulin and mucin domain containing−3 (TIM-3) blocking antibodies are currently being evaluated in clinical trials for solid and hematological malignancies. Despite its identification on T cells, TIM-3 is predominantly expressed by myeloid cells, including XCR1 + type I conventional dendritic cells (cDC1s). We have recently shown that TIM-3 blockade promotes expression of CXCR3 chemokine ligands by tumor cDCs, but how this drives a CD8 + T cell-dependent response to therapy is unclear. Methods: T cell infiltration, effector function, and spatial localization in relation to XCR1 + cDC1s were evaluated in a murine orthotopic mammary carcinoma model during response to TIM-3 blockade and paclitaxel chemotherapy. Mixed bone marrow chimeras and diphtheria toxin depletion were used to determine the role of specific genes in cDC1s during therapeutic responses. Results: TIM-3 blockade increased interferon-γ expression by CD8 + T cells without altering immune infiltration. cDC1 expression of CXCL9, but not CXCL10, was required for response to TIM-3 blockade. CXCL9 was also necessary for the increased proximity observed between CD8 + T cells and XCR1 + cDC1s during therapy. Tumor responses were dependent on cDC1 expression of interleukin-12, but not MHCI. Conclusions: TIM-3 blockade increases exposure of intratumoral CD8 + T cells to cDC1-derived cytokines, with implications for the design of therapeutic strategies using antibodies against TIM-3.