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TGFβ suppresses CD8+ T cell expression of CXCR3 and tumor trafficking

Author

Listed:
  • Andrew J. Gunderson

    (Earle A. Chiles Research Institute, Providence Cancer Institute)

  • Tomoko Yamazaki

    (Earle A. Chiles Research Institute, Providence Cancer Institute)

  • Kayla McCarty

    (Earle A. Chiles Research Institute, Providence Cancer Institute)

  • Nathaniel Fox

    (Earle A. Chiles Research Institute, Providence Cancer Institute)

  • Michaela Phillips

    (Earle A. Chiles Research Institute, Providence Cancer Institute)

  • Alejandro Alice

    (Earle A. Chiles Research Institute, Providence Cancer Institute)

  • Tiffany Blair

    (Earle A. Chiles Research Institute, Providence Cancer Institute)

  • Mark Whiteford

    (Earle A. Chiles Research Institute, Providence Cancer Institute
    The Oregon Clinic, Colon and Rectal Surgery Division)

  • David O’Brien

    (Earle A. Chiles Research Institute, Providence Cancer Institute
    The Oregon Clinic, Colon and Rectal Surgery Division)

  • Rehan Ahmad

    (Earle A. Chiles Research Institute, Providence Cancer Institute
    The Oregon Clinic, Colon and Rectal Surgery Division)

  • Maria X. Kiely

    (Earle A. Chiles Research Institute, Providence Cancer Institute
    The Oregon Clinic, Colon and Rectal Surgery Division)

  • Amanda Hayman

    (Earle A. Chiles Research Institute, Providence Cancer Institute
    The Oregon Clinic, Colon and Rectal Surgery Division)

  • Todd Crocenzi

    (Earle A. Chiles Research Institute, Providence Cancer Institute)

  • Michael J. Gough

    (Earle A. Chiles Research Institute, Providence Cancer Institute)

  • Marka R. Crittenden

    (Earle A. Chiles Research Institute, Providence Cancer Institute
    The Oregon Clinic, Radiation Oncology Division)

  • Kristina H. Young

    (Earle A. Chiles Research Institute, Providence Cancer Institute
    The Oregon Clinic, Radiation Oncology Division)

Abstract

Transforming growth factor beta (TGFβ) is a multipotent immunosuppressive cytokine. TGFβ excludes immune cells from tumors, and TGFβ inhibition improves the efficacy of cytotoxic and immune therapies. Using preclinical colorectal cancer models in cell type-conditional TGFβ receptor I (ALK5) knockout mice, we interrogate this mechanism. Tumor growth delay and radiation response are unchanged in animals with Treg or macrophage-specific ALK5 deletion. However, CD8αCre-ALK5flox/flox (ALK5ΔCD8) mice reject tumors in high proportions, dependent on CD8+ T cells. ALK5ΔCD8 mice have more tumor-infiltrating effector CD8+ T cells, with more cytotoxic capacity. ALK5-deficient CD8+ T cells exhibit increased CXCR3 expression and enhanced migration towards CXCL10. TGFβ reduces CXCR3 expression, and increases binding of Smad2 to the CXCR3 promoter. In vivo CXCR3 blockade partially abrogates the survival advantage of an ALK5ΔCD8 host. These data demonstrate a mechanism of TGFβ immunosuppression through inhibition of CXCR3 in CD8+ T cells, thereby limiting their trafficking into tumors.

Suggested Citation

  • Andrew J. Gunderson & Tomoko Yamazaki & Kayla McCarty & Nathaniel Fox & Michaela Phillips & Alejandro Alice & Tiffany Blair & Mark Whiteford & David O’Brien & Rehan Ahmad & Maria X. Kiely & Amanda Hay, 2020. "TGFβ suppresses CD8+ T cell expression of CXCR3 and tumor trafficking," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-15404-8
    DOI: 10.1038/s41467-020-15404-8
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    Cited by:

    1. Alessandra Castiglioni & Yagai Yang & Katherine Williams & Alvin Gogineni & Ryan S. Lane & Amber W. Wang & Justin A. Shyer & Zhe Zhang & Stephanie Mittman & Alan Gutierrez & Jillian L. Astarita & Minh, 2023. "Combined PD-L1/TGFβ blockade allows expansion and differentiation of stem cell-like CD8 T cells in immune excluded tumors," Nature Communications, Nature, vol. 14(1), pages 1-19, December.

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