Abstract 3468: Immunoproteasome expression and checkpoint blockade response in advanced non-small cell lung cancer

Abstract Responders to checkpoint blockade in Non Small Cell Lung Cancer (NSCLC) often feature an inflamed microenvironment prior to therapy. However, the complete set of molecular drivers connecting this histologic observation to enhanced tumor clearance remain enigmatic. In updated analysis of the Stand Up 2 Cancer-Mark Foundation (SU2C-MARK) Cohort - a collection of 393 patients with whole exome and/or RNA sequencing along with matched checkpoint blockade response annotation - we identify a prominent predictive role for inducible components of the immunoproteasome, a non-canonical peptide processing complex upstream of antigen presentation. Notably, these subunits are enriched as predictors relative to interferon-inducible genes as well as proteasome components in general, and are consistently associated with objective response, progression-free survival and overall survival. Expression of Immunoproteasome subunits associates positively with TCR (but not BCR) burden, supporting a mechanistic model in which enhanced immunoproteasome processivity leads to superior T-cell recognition. Furthermore, although they are known to be targets of interferon gamma (IFNɣ), we demonstrate that their expression is better modeled via a combination of IFNɣ and tumor necrosis factor-α (TNFα) levels, suggesting they may act as integrators of multiple cytokine cascades. Given the fact that the immunoproteasome can alter both antigen quantity as well as quality (including peptide cleavage site preference), the enhanced expression of this complex in the setting of checkpoint blockade response may have important implications for modeling of antigen presentation. These data also suggest novel strategies to enhance immune checkpoint blockade. Citation Format: Vivek Naranbhai, Arvind Ravi, Matthew Hellmann, Monica Arniella, Mark Holton, Samuel Freeman, Chip Stewart, Ignaty Leshchiner, Jaegil Kim, Yo Akiyama, Aaron Griffin, Natalie Vokes, Mustafa Sakhi, Vashine Kamesan, Hira Rizvi, Biagio Ricciuti, Patrick Forde, Valsamo Anagnostou, Jonathan Riess, Don Gibbons, Nathan Pennell, Vamsidhar Velcheti, Subba Digumarthy, Mari Mino-Kenudson, Andrea Califano, John Heymach, Roy Herbst, Julie Brahmer, Kurt Schalper, Victor Velculescu, Brian Henick, Naiyer Rizvi, Pasi Janne, Mark Awad, Andrew Chow, Benjamin Greenbaum, Marta Luksza, Alice Shaw, Jedd Wolchok, Nir Hacohen, Gad Getz, Justin Gainor. Immunoproteasome expression and checkpoint blockade response in advanced non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3468.