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TIM-3 blockade enhances IL-12-dependent antitumor immunity by promoting CD8 + T cell and XCR1 + dendritic cell spatial co-localization.
TIM-3 blockade enhances IL-12-dependent antitumor immunity by promoting CD8 + T cell and XCR1 + dendritic cell spatial co-localization.
- Source :
-
Journal for immunotherapy of cancer [J Immunother Cancer] 2022 Jan; Vol. 10 (1). - Publication Year :
- 2022
-
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 <superscript>+</superscript> 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 <superscript>+</superscript> T cell-dependent response to therapy is unclear.<br />Methods: T cell infiltration, effector function, and spatial localization in relation to XCR1 <superscript>+</superscript> 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.<br />Results: TIM-3 blockade increased interferon-γ expression by CD8 <superscript>+</superscript> 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 <superscript>+</superscript> T cells and XCR1 <superscript>+</superscript> cDC1s during therapy. Tumor responses were dependent on cDC1 expression of interleukin-12, but not MHCI.<br />Conclusions: TIM-3 blockade increases exposure of intratumoral CD8 <superscript>+</superscript> T cells to cDC1-derived cytokines, with implications for the design of therapeutic strategies using antibodies against TIM-3.<br />Competing Interests: Competing interests: BR has received payments from Merck & Co and Roche Farma SA for consulting. BR has previously had a sponsored research agreement with Tesaro: A GSK Company. JRC-G, KAR and BR have courtesy faculty appointment at the University of South Florida, Tampa, Florida.<br /> (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Details
- Language :
- English
- ISSN :
- 2051-1426
- Volume :
- 10
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Journal for immunotherapy of cancer
- Publication Type :
- Academic Journal
- Accession number :
- 34987021
- Full Text :
- https://doi.org/10.1136/jitc-2021-003571