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

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. [Display omitted] •Cancerous epithelial cells can express Acod1 and produce itaconate•Acod1 loss in αPD-1-resistant tumors resensitizes them to therapy•Acod1hi cells inhibit naive CD8+ T cell activation independent of itaconate•Acod1hi cells suppress T cells by secreting inhibitory peptides Schofield et al. report that cancer cells upregulate Acod1 as a survival strategy in response to αPD-1 therapy. Acod1hi cancer cells secrete inhibitory peptides that block the activation of naive CD8+ T cells. Loss of Acod1 resensitizes resistant tumors to αPD-1 ICB.