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

Jinming Yang, Chi Yan, Anna E. Vilgelm, Sheau-Chiann Chen, Gregory D. Ayers, Christopher A. Johnson and Ann Richmond
Jinming Yang
1Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, Tennessee.
2Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee.
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Chi Yan
2Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee.
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  • ORCID record for Chi Yan
Anna E. Vilgelm
2Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee.
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Sheau-Chiann Chen
3Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee.
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Gregory D. Ayers
3Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee.
4Division of Cancer Biostatistics, Department of Biostatistics, Vanderbilt University, Nashville, Tennessee.
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Christopher A. Johnson
1Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, Tennessee.
2Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee.
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Ann Richmond
1Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, Tennessee.
2Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee.
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  • For correspondence: Ann.Richmond@vanderbilt.edu
DOI: 10.1158/2326-6066.CIR-20-0312 Published February 2021
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Abstract

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.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Immunology Research Online (http://cancerimmunolres.aacrjournals.org/).

  • Cancer Immunol Res 2021;9:200–13

  • Received April 20, 2020.
  • Revision received August 21, 2020.
  • Accepted November 5, 2020.
  • Published first November 23, 2020.
  • ©2020 American Association for Cancer Research.
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Cancer Immunology Research: 9 (2)
February 2021
Volume 9, Issue 2
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Targeted Deletion of CXCR2 in Myeloid Cells Alters the Tumor Immune Environment to Improve Antitumor Immunity
Jinming Yang, Chi Yan, Anna E. Vilgelm, Sheau-Chiann Chen, Gregory D. Ayers, Christopher A. Johnson and Ann Richmond
Cancer Immunol Res February 1 2021 (9) (2) 200-213; DOI: 10.1158/2326-6066.CIR-20-0312

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Targeted Deletion of CXCR2 in Myeloid Cells Alters the Tumor Immune Environment to Improve Antitumor Immunity
Jinming Yang, Chi Yan, Anna E. Vilgelm, Sheau-Chiann Chen, Gregory D. Ayers, Christopher A. Johnson and Ann Richmond
Cancer Immunol Res February 1 2021 (9) (2) 200-213; DOI: 10.1158/2326-6066.CIR-20-0312
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