Abstract 2334: Inhibition of DHFR modulates anti-tumor immunity

Abstract Lung cancer is the second most common type of cancer in both men and women and has the highest mortality rate. Non-small cell lung cancer (NSCLC) makes up most cases. Immune checkpoint inhibitors have significantly improved the clinical management of some NSCLC cases, yet many lung cancer patients still fail to respond to conventional immunotherapy. Therefore, more research is needed to characterize cellular pathways contribute to immune checkpoint inhibitor (ICI) resistance in NSCLC patients. Dysregulated cellular metabolism is a common feature of many cancer types, and metabolites are now known to modulate several functions inside cells such as signaling pathways and epigenetic control of gene expression. Therefore, targeting tumor metabolism may be able to combat NSCLC immunotherapy resistance. To identify potential metabolic pathways involved in the anti-tumor immune response, we employed a metabolic inhibitor-based drug screen in human NSCLC cell lines and tested for expression changes in a panel of known immune regulator genes. Notably, pharmacologic inhibition of dihydrofolate reductase (DHFR) downregulated the mRNA expression of anti-phagocytic surface protein cluster of differentiation 24 (CD24) in lung cancer cells. In line with this, shRNA knockdown and overexpression of DHFR, decreased and increased CD24 RNA and protein levels, respectively. These results show that the metabolic enzyme DHFR is involved in CD24 gene expression. Cancer cells heavily rely on DHFR for enhanced nucleotide biosynthesis to facilitate rapid tumor growth, and DHFR inhibitors are already used in the clinic for cancer therapy. This study highlights a novel interaction between reprogrammed cancer metabolism and the anti-tumor immune response, with possible clinical implications for DHFR inhibitors such as methotrexate in combination with conventional cancer immunotherapy agents. Citation Format: Austin Boese, Isabelle Young, Jihoon Kang, Courteney Malin, Jung Seok Hwang, Sumin Kang. Inhibition of DHFR modulates anti-tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2334.