PSME4 abrogates anti-tumor immunity and promotes resistance to immunotherapy in NSCLC

Immunoproteasomes have numerous functions including promoting cellular inflammation, antigen presentation and tumor immunogenicity. However, the precise mechanisms by which their activity is regulated is not fully understood. By profiling the degradation landscape in lung cancer tissue and adjacent controls we found tumor-specific alterations and increased proteasomal degradation in non-small cell lung cancer (NSCLC). Our analysis revealed that the proteasome activator, PA200/PSME4, is increased in NSCLC and associated with poor survival. Here we found that PSME4 directly binds to and attenuates the activity of the immunoproteasome. This antagonistic interaction promotes IL6 secretion which in turn abrogates anti-tumor immunity and drives tumor progression in vivo. Consistent with this reduction in tumor immunogenicity, we found that the ratio between PSME4 and the immunoproteasome was significantly associated with poor response to immune checkpoint blockade. Collectively, our results provide a novel paradigm where the proteasome regulator PSME4 asymmetrically modulates the balance between immuno- and constitutive proteasome activity, thereby promoting a ‘cold’ tumor state. This offers a novel understanding for regulatory mechanisms underlying tumor proteostasis and promotes PSME4 as a novel target for sensitizing response to immunotherapy in NSCLC and other cancer types.