Project description:Alterations in cellular antigen processing and presenting machinery has gained increased interest as a hallmark of cancer-related inflammation. Growing evidence suggest that proteasome composition and immunoproteasome expression can influence the efficacy of cancer therapies. By applying proteasome foot-printing to clinical samples of Non Small Cell lung Cancer (NSCLC), we found tumor specific alterations in degradation products and increased expression of the proteasome regulator, PA200. We show that increased levels of PA200 alter the cleavage specificities of proteasomal-cleaved peptides and reduce antigenicity. We found that smoking-induced expression of PA200 abrogated immunoproteasome activity and is associated with poor survival. As immunotherapy is becoming a common treatment of NSCLC, we hypothesized that PA200 expression may contribute to resistance mechanism to immunotherapy. Consistent with this possibility, we found that the ratio between PA200 and the immunoproteasome subunit PSMB10, and not their absolute levels, were significantly associated with poor response to Durvalamab. Induced reduction in PA200 in vivo was associated with increased immune infiltration and attenuated tumor growth.
Project description:To discover potential plasma biomarkers, we are aiming to explore circulating and tumor-derived proteins related to the efficacy of anti-PD-1 treatment to select the optimal NSCLC patients for immunotherapy via DIA.
Project description:Disruption in proteostasis is a hallmark of cancer, with aberrations in proteasome-mediated degradation highly implicated in this malignancy. Proteasomes further bear critical importance in tumor immunogenicity by regulating inflammatory signaling, promoting immune cell activation and playing a crucial role in antigen processing and presentation. Indeed, response to immunotherapy in melanoma patients has been recently linked to increased expression of immunoproteasomes, a specialized form of proteasomes that are upregulated under inflammatory conditions. Yet, the percentage of patients that respond to therapy remains low, and the underlying mechanisms driving resistance remain poorly understood. Further, comprehensive analysis of the role proteasomes play in the pathophysiology of cancer and as a modulator of anti-tumor immunity is remains lacking. Here, we show that proteasome complex composition varies across cancer types and can be used to stratify patient response to immunotherapy. Specifically, we found that the proteasome regulator PSME4 is upregulated in NSCLC and associated with poor prognosis. We show that PSME4 alters proteasome activity and antigen processing attenuating the antigenic diversity and presentation. Through exacting biochemical assays, proteasome profiling of patient-derived NSCLC samples, combined with scRNA-seq, immunopeptidomics and in vivo analyses we uncovered a novel mechanism of immune evasion mediated by PSME4, which promotes an immunosuppressive tumor microenvironment and abrogates anti-tumor immunity. Collectively, our approach may be adapted to other cancer types and pathological settings and affords a novel paradigm by which proteasome composition heterogeneity should be examined and targeted in the context of precision oncology.