Abstract 379: Landscape of HIF-1α expression across 24,186 solid tumors using comprehensive immune profiling

Abstract Background: Transcription factor Hypoxia Inducible Factor-1α (HIF-1α) is a key regulator of various cellular and systemic responses to hypoxia, with HIF-1α mediated pathways playing an important role in tumor progression and metastasis. Recent studies have highlighted the correlation between HIF-1α expression with tumor cell survival, angiogenesis, and invasion. In this study, we explore the landscape of HIF-1α expression across 35 solid tumor histologies, its co-expression with immune checkpoint and angiogenesis-related genes, as well as its association with outcomes from a retrospective cohort of patients with non-small cell lung cancer (NSCLC) treated with pembrolizumab. Methods: A discovery cohort of 24,186 solid tumors across 35 types were evaluated by comprehensive immune profiling assay. HIF-1α gene expression was normalized and ranked against a reference population of 735 samples yielding a percentile rank values [0-100], with rank classified as high (≥75), moderate (≥25 and <75) and low (<25). We investigated the distribution of HIF-1α expression, cellular proliferation signature, and co-expression with other immunotherapy targets using Spearman correlations (rs). Additionally, Kaplan-Meier analysis and Chi-squared tests were utilized for overall survival (OS), progression free survival (PFS) and objective response rate (ORR) differences in a retrospective cohort of 72 patients with NSCLC, treated with pembrolizumab. Results: Pan-cancer analysis confirmed a broad distribution of HIF-1α expression, with highest median expression levels observed in brain and central nervous system (CNS) (median=64), thyroid (median=49) and uterine (median=42) cancers. Significant associations (p<0.001) were observed between PD-L1 positivity (TPS≥1%, CPS≥1) and HIF-1α expression, with 60% of HIF-1α high cases (n=1,314/2,193) being PD-L1 positive, whereas 53% of HIF-1α low cases (n=4,834/9,135) were PD-L1 negative. Significant correlations (p<0.05) of ranked expression of HIF-1α with immune checkpoint blockage targets like PD-1 and CTLA-4, as well as angiogenesis-related genes like VEGFA and PTEN were observed. Within our pembrolizumab-treated retrospective cohort, there were no significant differences in OS and PFS between HIF-1α high and HIF-1α low tumors. However, the response to pembrolizumab was significantly higher in HIF-1α low tumors (ORR=58.82%, p<0.01) compared to HIF-1α high tumors. Conclusion: In clinically tested solid tumors, HIF-1α showed a dynamic expression range, with highest levels observed in brain, thyroid and uterine cancers. Significant co-expression of HIF-1α with various downstream genes, especially angiogenesis-related genes, enabled identification of gene signatures that characterize the hypoxic tumor microenvironment and may aid in the development of novel combination therapy strategies. Citation Format: Hardik I. Parikh, Sarabjot Pabla, Maria-Fernanda Senosain, Robert Seager, Erik Vanroey, Shuang Gao, Yamuna Pulivendula, Paul DePietro, Mary Nesline, Durgapras Dash, Jeffrey Conroy, Stephanie Hastings, Heidi Ko, Kyle Strickland, Rebecca Previs, Eric Severson, Taylor Jensen, Shakti Ramkissoon, Marcia Eisenberg, Brian Caveney. Landscape of HIF-1α expression across 24,186 solid tumors using comprehensive immune profiling [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 379.