TIM-3 Regulates CD103+ Dendritic Cell Function and Response to Chemotherapy in Breast Cancer

Abstract

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.

Tumor Dendritic Cells (DCs) Derived from Precursors of Conventional DCs Are Dispensable for Intratumor CTL Responses

“…Several reports also highlight their importance in presenting tumor Ags to intratumor CTLs and in attracting CTLs to the TME (18)(19)(20). We found that depletion of pre-cDC-derived DCs in Zbtb46-DTR bone marrow chimeras abolished CTL proliferation and expansion in TDLNs, confirming their dominance in presenting tumor Ags in lymphoid tissues.…”

“…This interest has been bolstered by analyses of The Cancer Genome Atlas showing that patient survival for many cancers correlates positively with the gene expression signature for human DC1 (18,20,39). Whether this correlation relates to better priming of tumor Agspecific T cells in lymphoid tissues, the TME, or both has been difficult to discern.…”

“…Intratumor DCs also promote the expansion and function of tumor-infiltrating CTLs (17,18); however, controversy persists over which DC subpopulation is involved. Several reports have emphasized the dominance of DC1 based on their robust Ag cross-presenting activity (as compared with DC2 and other myeloid populations) and their apparent importance in inhibiting tumor growth in mice treated with adoptive CTL therapy (18)(19)(20). By contrast, Ma et al (21) reported that treating mice with anti-CD11b Abs eliminated the immune-mediated benefits of anthracycline chemotherapy, whereas loss of DC1 in tumors implanted into BATF3 2/2 mice did not attenuate this effect of chemotherapy.…”

ACKR4 restrains antitumor immunity by regulating CCL21

“…Once primed, expression of CXCR3 by effector CD8 + T cells enables their recruitment into the tumor microenvironment (Mikucki et al, 2015), where in the absence of expression of inhibitory molecules, such as PD-1, they can mediate tumor destruction. This CD8 + T cell recruitment is thought to be largely controlled by CD103 + DCs at the tumor site, which have been shown to be the predominant source of the ligands CXCL9 and CXCL10 in multiple tumors (de Mingo Pulido et al, 2018; Spranger et al, 2017). Thus, via their control of multiple facets of the CD8 + T cell response, CD103 + DCs are a key determinant of the magnitude of the antitumor response, and understanding their regulation in tumor settings is of great therapeutic importance.…”

TIM-3 expression in breast cancer

“…TIM-3 immunohistochemistry was conducted with anti-TIM-3 rabbit monoclonal antibody clone D5D5R from Cell Signaling (Cat# 45208) as employed in other publications 21,33,49,50 , here using a Ventana Ultra automated stainer (Ventana Medical Systems) in concordance with manufacturer’s protocol. In brief, slides underwent antigen retrieval with Standard Cell Conditioning 1 reagent (Ventana Medical Systems) followed by 60 minutes of primary antibody incubation (applied at 1:50 dilution) with no heat, and visualized using a chromoMap DAB detection kit (Ventana Medical Systems).…”