De Mingo Pulido et al. found that TIM-3 is highly expressed on tumor-infiltrating CD103+ dendritic cells (cDC1s) and that anti-TIM-3 antibody mediates antitumor activity through the CXCL9/CXCR3 axis, potentially by upregulating CXCL9 expression by cDC1s, which enhances Granzyme B expression by CD8+ T cells. In mouse models of breast cancer, anti-TIM-3 antibody increases cell death within tumors and improves response to paclitaxel chemotherapy without increasing toxicity, indicating a possible clinical application.
Intratumoral CD103(+) dendritic cells (DCs) are necessary for anti-tumor immunity. Here we evaluated the expression of immune regulators by CD103(+) DCs in a murine model of breast cancer and identified 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 evidence 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 DCs during combination therapy, and therapeutic efficacy was ablated by CXCR3 blockade, Batf3 deficiency, or Irf8 deficiency.
Author Info: (1) Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive SRB-2, Tampa, FL 33612, USA. (2) Department of Immunology, H. Lee Moffitt Ca
Author Info: (1) Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive SRB-2, Tampa, FL 33612, USA. (2) Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive SRB-2, Tampa, FL 33612, USA; Cancer Biology PhD Program, University of South Florida, Tampa, FL 33620, USA. (3) Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive SRB-2, Tampa, FL 33612, USA. (4) Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive SRB-2, Tampa, FL 33612, USA; Department of Breast Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA. (5) Department of Medicine and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94143, USA. (6) Department of Pathology, University of California, San Francisco, CA 94143, USA. (7) Department of Cell, Developmental & Cancer Biology, and Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA. (8) Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive SRB-2, Tampa, FL 33612, USA; Department of Breast Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA. Electronic address: brian.ruffell@moffitt.org.
