Using mice with Cxcr2-null myeloid cells, Yang et al. showed that xenografts of melanoma and breast cancer lung metastases had intratumoral reduction of MDSCs, M2-like macrophages, and CD4+ Treg cells, and increases of B1b cells producing CXCL11, CD4+ TEM cells, and effector CD8+ T cells, which inhibited tumor growth. Depleting B220+ cells or CD8+ T cells reversed antitumor effects. CXCR2 small-molecule antagonism of wild-type mice recapitulated these effects, and tumor growth inhibition was enhanced by anti-PD-1. TCGA analysis showed that B220 and CXCL11 expression positively correlate with better outcomes for breast cancer and melanoma.
Contributed by Paula Hochman
ABSTRACT: Recruitment of myeloid-derived suppressor cells (MDSCs) into the tumor microenvironment (TME) contributes to cancer immune evasion. MDSCs express the chemokine receptor CXCR2, and inhibiting CXCR2 suppresses the recruitment of MDSCs into the tumor and the pre-metastatic niche. Here we compared the growth and metastasis of melanoma and breast cancer xenografts in mice exhibiting or not exhibiting targeted deletion of Cxcr2 in myeloid cells (CXCR2myeΔ/Δ vs. CXCR2 myeWT). Detailed analysis of leukocyte populations in peripheral blood and in tumors from CXCR2myeΔ/Δ mice revealed that loss of CXCR2 signaling in myeloid cells resulted in reduced intratumoral MDSCs and increased intratumoral CXCL11. The increase in intratumoral CXCL11 was derived in part from tumor-infiltrating B1b cells. The reduction in intratumoral MDSCs coupled with an increase in intratumoral B1b cells expressing CXCL11 resulted in enhanced infiltration and activation of effector CD8+ T cells in the TME of CXCR2myeΔ/Δ mice, accompanied by inhibition of tumor growth in CXCR2myeΔ/Δ mice compared to CXCR2myeWT littermates. Treatment of tumor-bearing mice with a CXCR2 antagonist (SX-682) also inhibited tumor growth, reduced intratumoral MDSCs, and increased intratumoral B1b cells expressing CXCL11, leading to an increase in activated CD8+ T cells in the tumor. Depletion of B220+ cells or depletion of CD8+ T cells reversed the tumor inhibitory properties in CXCR2myeΔ/Δ mice. These data revealed a mechanism by which loss of CXCR2 signaling in myeloid cells modulates antitumor immunity through decreasing MDSCs and enriching CXCL11-producing B1b cells in the TME, which in turn increases CD8+ T-cell recruitment and activation in tumors.
Author Info: (1) Pharmacology, Vanderbilt University Ann.Richmond@vanderbilt.edu. (2) Pharmacology, Vanderbilt University. (3) Pharmacology, Vanderbilt University. (4) Pathology, Ohio State Uni
Author Info: (1) Pharmacology, Vanderbilt University Ann.Richmond@vanderbilt.edu. (2) Pharmacology, Vanderbilt University. (3) Pharmacology, Vanderbilt University. (4) Pathology, Ohio State University. (5) Biostatistics, Vanderbilt University Medical Center. (6) Biostatistics, Vanderbilt University School of Medicine. (7) Pharmacology, Vanderbilt University Medical Center.
