Targeted Deletion of CXCR2 in Myeloid Cells Alters the Tumor Immune Environment to Improve Antitumor Immunity

Cancer Immunol Res. 2021 Feb;9(2):200-213. doi: 10.1158/2326-6066.CIR-20-0312. Epub 2020 Nov 11.


Recruitment of myeloid-derived suppressor cells (MDSC) 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 premetastatic 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. CXCR2myeWT). 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 with 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.

Publication types

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

MeSH terms

  • Animals
  • Antineoplastic Agents, Immunological / pharmacology
  • Breast Neoplasms / immunology
  • Breast Neoplasms / pathology
  • Breast Neoplasms / therapy*
  • CD8-Positive T-Lymphocytes / immunology*
  • Cell Line, Tumor
  • Chemokine CXCL11 / metabolism*
  • Humans
  • Melanoma / immunology
  • Melanoma / pathology
  • Melanoma / therapy*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myeloid-Derived Suppressor Cells / immunology*
  • Receptors, Interleukin-8B / genetics*
  • Receptors, Interleukin-8B / metabolism
  • Signal Transduction
  • Tumor Microenvironment / drug effects
  • Tumor Microenvironment / immunology
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents, Immunological
  • CXCL11 protein, human
  • CXCR2 protein, human
  • Chemokine CXCL11
  • Receptors, Interleukin-8B