TIM-3 blockade enhances IL-12-dependent antitumor immunity by promoting CD8+ T cell and XCR1+ dendritic cell spatial co-localization

J Immunother Cancer. 2022 Jan;10(1):e003571. doi: 10.1136/jitc-2021-003571.


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.

Keywords: CD8-positive T-lymphocytes; breast neoplasms; costimulatory and inhibitory T-cell receptors; dendritic cells; tumor microenvironment.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / immunology*
  • Dendritic Cells / immunology*
  • Hepatitis A Virus Cellular Receptor 2 / antagonists & inhibitors*
  • Humans
  • Immunotherapy / methods*
  • Interleukin-12 / metabolism*
  • Mice
  • Receptors, Chemokine / metabolism*
  • Signal Transduction


  • Havcr2 protein, mouse
  • Hepatitis A Virus Cellular Receptor 2
  • Receptors, Chemokine
  • XC chemokine receptor 1, mouse
  • Interleukin-12