Abstract 7528: Coordinated regulation of critical immune checkpoint proteins by the integrated stress response (ISR) pathway in lung cancer

Abstract Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide. Despite recent advances, high rates of recurrence highlight the need for novel treatment options. Groundbreaking discoveries in identifying and exploiting the PD-1/PD-L1 (Programmed Death 1/Programmed Death Ligand 1) immune checkpoint have resulted in the approval of monoclonal antibodies that disrupt this interaction as a first-line therapy for lung cancer patients. However, only ~20% of NSCLC patients benefit from checkpoint blockade. A critical question remains as to what mechanisms facilitate resistance to PD-1/PD-L1 therapy and whether other immune checkpoints or pathways can be pursued clinically in combination with this therapy. The integrated stress response (ISR) pathway represents an emerging therapeutic vulnerability. The ISR is a generalized response to maintain cellular homeostasis, and is known to be activated by hypoxia, heme deprivation, amino acid starvation, and oncogenic activation. We previously demonstrated that ISR activation potently induces PD-L1 in NSCLC and suppression of anti-tumor immunity (Suresh et al, Nature Cancer, 2020). We discovered that ISR pathway activation enhances PD-L1 translation through the bypass of inhibitory upstream open reading frames (uORFs) in the PD-L1 5' UTR and a mechanistic link to the translation initiation factor eIF5B. Our latest studies demonstrate that the immune checkpoint protein, CD155 (Cluster of Differentiation 155), is induced by ISR activation. We find that both PD-L1 and CD155 are induced by multiple arms of the ISR pathway, and CD155 harbors inhibitory uORFs in its 5' UTR. Importantly, we observed a significant correlation between PD-L1 and CD155 expression in a panel of primary human lung adenocarcinomas. We further demonstrated that ISR activation inhibits T cell function in vitro and promotes tumor growth in the CMT167 syngeneic mouse model. Analysis of immune cell infiltration using mass cytometry in this in vivo model is ongoing. Currently, we are determining the extent to which ISR inhibition suppresses tumorigenesis by promoting anti-tumor immunity and whether this may synergize with existing immune checkpoint therapies. Overall, these studies will set the stage for determining whether inhibition of the ISR pathway alone or in combination with immune checkpoint blockade will benefit lung cancer patients. Our studies may also lead to new therapeutic approaches to trigger anti-cancer immune responses and improve current strategies. Citation Format: Shayna Elizabeth Thomas-Jardin, Shruthy Suresh, Cheryl Lewis, Chul Ahn, Bret M. Evers, John D. Minna, Kathryn A. O'Donnell. Coordinated regulation of critical immune checkpoint proteins by the integrated stress response (ISR) pathway in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7528.