HIF1A expression correlates with increased tumor immune and stromal signatures and aggressive phenotypes in human cancers

Background Although many studies have revealed essential roles of HIF1A (hypoxia inducible factor 1 subunit alpha) in regulating various pathways associated with cancer development, a systematic investigation of associations of HIF1A expression with tumor immunity, the tumor microenvironment and other tumor phenotypes in pan-cancer is lacking. Methods Using cancer genomics datasets of 10 cancer cohorts from the Cancer Genome Atlas (TCGA) program, we investigated associations of HIF1A expression with tumor immune and stromal signatures, and various tumor phenotypes, including cell proliferation, stemness, epithelial-mesenchymal transition (EMT), tumor purity, oncogenic signaling, and clinical outcomes. Results HIF1A upregulation was found to be associated with increased immune and stromal signatures, aggressive phenotypes, and worse survival rates in various cancers. Moreover, HIF1A upregulation was not only associated with activation of various oncogenic signaling pathways, but also with increased tumor suppressive signatures, including apoptosis and anti-tumor immune response, indicative of a dual role of HIF1A in cancer development. However, HIF1A expression showed a stronger correlation with immune-inhibiting signatures than with immune-promoting signatures. Furthermore, HIF1A expression was found to be positively associated with both tumor immune infiltration and PD-L1 expression, indicating that tumors with elevated expression of HIF1A may exhibit a more active immunotherapy response. This indication was substantiated in a kidney cancer cohort receiving anti-PD-1/PD-L1 immunotherapy. Conclusions HIF1A upregulation correlates with increased tumor immune and stromal signatures and aggressive phenotypes in human cancers. Our analysis may provide new insights into the role of HIF1A in tumor biology and clinical management.