Purpose: Clear cell renal cell carcinoma (ccRCC) is frequently associated with inactivation of the von Hippel–Lindau tumor suppressor, resulting in activation of HIF-1a and HIF-2a. The current paradigm, established using mechanistic cell-based studies, supports a tumor promoting role for HIF-2a, and a tumor suppressor role for HIF-1a. However, few studies have comprehensively examined the clinical relevance of this paradigm. Furthermore, the hypoxia-associated factor (HAF), which regulates the HIFs, has not been comprehensively evaluated in ccRCC. Experimental Design: To assess the involvement of HAF/HIFs in ccRCC, we analyzed their relationship to tumor grade/stage/ outcome using tissue from 380 patients, and validated these associations using tissue from 72 additional patients and a further 57 patients treated with antiangiogenic therapy for associations with response. Further characterization was performed using single-cell mRNA sequencing (scRNA-seq), RNA-in situ hybridization (RNA-ISH), and IHC. Results: HIF-1a was primarily expressed in tumor-associated macrophages (TAMs), whereas HIF-2a and HAF were expressed primarily in tumor cells. TAM-associated HIF-1a was significantly associated with high tumor grade and increased metastasis and was independently associated with decreased overall survival. Furthermore, elevated TAM HIF-1a was significantly associated with resistance to antiangiogenic therapy. In contrast, high HAF or HIF-2a were associated with low grade, decreased metastasis, and increased overall survival. scRNA-seq, RNA-ISH, and Western blotting confirmed the expression of HIF-1a in M2-polarized CD163-expressing TAMs. Conclusions: These findings highlight a potential role of TAM HIF-1a in ccRCC progression and support the reevaluation of HIF-1a as a therapeutic target and marker of disease progression.
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