Cell Reports (Apr 2024)

Acod1 expression in cancer cells promotes immune evasion through the generation of inhibitory peptides

  • James H. Schofield,
  • Joseph Longo,
  • Ryan D. Sheldon,
  • Emma Albano,
  • Abigail E. Ellis,
  • Mark A. Hawk,
  • Sean Murphy,
  • Loan Duong,
  • Sharif Rahmy,
  • Xin Lu,
  • Russell G. Jones,
  • Zachary T. Schafer

Journal volume & issue
Vol. 43, no. 4
p. 113984

Abstract

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Summary: Targeting programmed cell death protein 1 (PD-1) is an important component of many immune checkpoint blockade (ICB) therapeutic approaches. However, ICB is not an efficacious strategy in a variety of cancer types, in part due to immunosuppressive metabolites in the tumor microenvironment. Here, we find that αPD-1-resistant cancer cells produce abundant itaconate (ITA) due to enhanced levels of aconitate decarboxylase (Acod1). Acod1 has an important role in the resistance to αPD-1, as decreasing Acod1 levels in αPD-1-resistant cancer cells can sensitize tumors to αPD-1 therapy. Mechanistically, cancer cells with high Acod1 inhibit the proliferation of naive CD8+ T cells through the secretion of inhibitory factors. Surprisingly, inhibition of CD8+ T cell proliferation is not dependent on the secretion of ITA but is instead a consequence of the release of small inhibitory peptides. Our study suggests that strategies to counter the activity of Acod1 in cancer cells may sensitize tumors to ICB therapy.

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