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The immune checkpoint B7x expands tumor-infiltrating Tregs and promotes resistance to anti-CTLA-4 therapy

Author

Listed:
  • Peter John

    (Albert Einstein College of Medicine)

  • Marc C. Pulanco

    (Albert Einstein College of Medicine)

  • Phillip M. Galbo

    (Albert Einstein College of Medicine)

  • Yao Wei

    (Albert Einstein College of Medicine)

  • Kim C. Ohaegbulam

    (Albert Einstein College of Medicine)

  • Deyou Zheng

    (Albert Einstein College of Medicine
    Albert Einstein College of Medicine)

  • Xingxing Zang

    (Albert Einstein College of Medicine
    Albert Einstein College of Medicine
    Albert Einstein College of Medicine)

Abstract

Immune checkpoint molecules play critical roles in regulating the anti-tumor immune response, and tumor cells often exploit these pathways to inhibit and evade the immune system. The B7-family immune checkpoint B7x is widely expressed in a broad variety of cancer types, and is generally associated with advanced disease progression and poorer clinical outcomes, but the underlying mechanisms are unclear. Here, we show that transduction and stable expression of B7x in multiple syngeneic tumor models leads to the expansion of immunosuppressive regulatory T cells (Tregs). Mechanistically, B7x does not cause increased proliferation of Tregs in tumors, but instead promotes the conversion of conventional CD4+ T cells into Tregs. Further, we find that B7x induces global transcriptomic changes in Tregs, driving these cells to adopt an activated and suppressive phenotype. B7x increases the expression of the Treg-specific transcription factor Foxp3 in CD4+ T cells by modulating the Akt/Foxo pathway. B7x-mediated regulation of Tregs reduces the efficacy of anti-CTLA-4 treatment, a therapeutic that partially relies on Treg-depletion. However, combination treatment of anti-B7x and anti-CTLA-4 leads to synergistic therapeutic efficacy and overcomes the B7x-mediated resistance to anti-CTLA-4. Altogether, B7x mediates an immunosuppressive Treg-promoting pathway within tumors and is a promising candidate for combination immunotherapy.

Suggested Citation

  • Peter John & Marc C. Pulanco & Phillip M. Galbo & Yao Wei & Kim C. Ohaegbulam & Deyou Zheng & Xingxing Zang, 2022. "The immune checkpoint B7x expands tumor-infiltrating Tregs and promotes resistance to anti-CTLA-4 therapy," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30143-8
    DOI: 10.1038/s41467-022-30143-8
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    1. Saiyu Hang & Donggi Paik & Lina Yao & Eunha Kim & Jamma Trinath & Jingping Lu & Soyoung Ha & Brandon N. Nelson & Samantha P. Kelly & Lin Wu & Ye Zheng & Randy S. Longman & Fraydoon Rastinejad & A. Slo, 2019. "Bile acid metabolites control TH17 and Treg cell differentiation," Nature, Nature, vol. 576(7785), pages 143-148, December.
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