TIM-3 regulates cDC1 function and response to chemotherapy in breast cancer
 
Alvaro de Mingo-Pulido¹, Alycia Gardner^1,3, Vivian Lee¹, Shandi Hiebler¹, Hatem Soliman^1,2, Hope S. Rugo⁴, Matthew F. Krummel⁵, Lisa M. Coussens⁶, Brian Ruffel^1,2
1Department of Immunology and ²Breast Oncology, H. Lee Moffitt Cancer Center; ³Cancer Biology PhD Program, University of South Florida; ⁴Department of Medicine and Helen Diller Family Comprehensive Cancer, ⁵Department of Pathology, University of California, San Francisco; ⁶Department of Cell, Developmental & Cancer Biology, and Knight Cancer Institute, Oregon Health & Science University
  
Dendritic cells are required to prime a de novo T cell response against tumors, where intratumoral CD103+ conventional dendritic cells (cDC1s) have been described to be necessary for anti-tumor immunity. Here we evaluated expression of immune regulators by intratumoral cDC1s in a murine model of breast cancer and identify expression of TIM-3 as a target for therapy. Anti-TIM-3 antibody improved response to paclitaxel chemotherapy in models of triple-negative and luminal B disease, with no sign of toxicity. Combined efficacy was CD8+ T cell-dependent and associated with increased granzyme B expression; however, TIM-3 expression was predominantly localized to myeloid cells in both human and murine tumors. Gene expression analysis identified upregulation of Cxcl9 within intratumoral cDCs during combination therapy, an observation that was mimicked in vitro with splenic cDC1s cultured with tumor cell debris and anti-TIM-3. Therapeutic efficacy was ablated by CXCR3 blockade, Batf3- or Irf8-deficiency, or DC depletion using diphtheria toxin, demonstrating that cDC1s are a functional target of TIM-3 blockade. These findings expand upon the potential targets of TIM-3 antibodies currently in clinical trials, and offer a rationale for combinatorial studies with chemotherapy in breast cancer and other solid malignancies.