Author:
Schofield James H.,Longo Joseph,Sheldon Ryan D.,Albano Emma,Hawk Mark A.,Murphy Sean,Duong Loan,Rahmy Sharif,Lu Xin,Jones Russell G.,Schafer Zachary T.
Abstract
AbstractTargeting 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 (TME). 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 naïve CD8+T cells through the secretion of inhibitory factors. Surprisingly, inhibition of CD8+T cell proliferation is not dependent on 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.
Publisher
Cold Spring Harbor Laboratory