Abstract PO033: Regulation of immune checkpoint proteins in NSCLC adenocarcinoma

Abstract

Lung cancer is the leading cause of cancer-related deaths in both men and women. Approximately 85% of lung cancers are non-small cell lung cancer (NSCLC), with adenocarcinoma (adenoCa) being the main subtype. Well-defined mutational signatures of various lung cancer subtypes have been exploited for targeted therapies, but cancer cells often acquire resistance to these treatments, which could be mediated by the inflammatory tumor microenvironment (TME). Inflammation within the TME is known to promote cancer progression and therapy resistance. The inflammatory cytokine, interleukin-1 beta (IL-1β) is elevated in the TME of several cancers and correlates with poor outcomes. In NSCLC patients, serum IL-1β is elevated relative to normal subjects; within the same patient, IL-1β is elevated in the tumor relative to adjacent non-tumor tissue. Significantly, the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) showed that blockade of IL-1 signaling could drastically reduce lung cancer incidence and mortality. Interestingly, we observed that NSCLC adenoCa cell lines H1838, H2228, H2347, HCC4150 and HCC827 have significantly higher basal expression of the Type 1 IL-1 receptor (IL-1R1), relative to immortalized normal Human Bronchial Epithelial Cell (HBEC-3KT) and Human Small Airway Epithelial Cell (HSAEC-1KT) lines, suggesting that adenoCa cells are primed to respond to IL-1 signaling. Cancer cells can promote immunosuppression through the expression of immune checkpoint proteins (ICPs). Previously, we identified several ICPs, including programmed death-ligand 1 (PD-L1), tryptophan 2,3-dioxygenase 2 (TDO2), indoleamine 2, 3-dioxygenase 1 (IDO1) and growth differentiation factor 15 (GDF15), that were developmentally upregulated by transcription factor nuclear factor erythroid 2-related factor 2 (NRF2/NFE2L2) in human fetal lung epithelial cells during differentiation in culture. Importantly, genomic studies have revealed that >20% of lung adenoCa harbor mutations in NRF2 or its inhibitor KEAP1, which cause NRF2 activation. Lung adenoCa with signatures of increased NRF2 activation manifest reduced immune cell infiltration, suggesting that increased expression of NRF2 might create a more permissive immune cell environment, resulting in evasion and tolerance to the host immune system. Given that IL-1β induces ROS which can activate NRF2, we hypothesized that IL-1β present in the TME may enhance expression of NRF2 and ICPs in NSCLC adenoCa. We found that increased expression of ICPs in adenoCa cell lines H1838, H2228, H2347, HCC4150 and HCC827 compared to HBEC-3KT and HSAEC-1KT cells was correlated with significantly increased expression of NRF2. When these adenoCa cell lines were treated with IL-1β, we observed a marked induction in NRF2 and ICP mRNA and protein levels. Taken together our studies indicate that NSCLC adenoCa cells are primed to respond to IL-1 signaling which induces NRF2 and ICPs to promote tumor cell survival through immunosuppression. Citation Format: Afshan Fathima Nawas, Ritu Mishra, Carole R. Mendelson. Regulation of immune checkpoint proteins in NSCLC adenocarcinoma [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr PO033.