Hypoxia and tumor associated macrophages shape response to immune and angiogenesis-targeted therapies in metastatic clear cell renal cell carcinoma 3738

Abstract Description Clear cell renal cell carcinoma (ccRCC) is driven by biallelic loss of VHL, leading to pseudohypoxia & elevated angiogenesis. Thus, anti-angiogenesis tyrosine kinase inhibitors (TKI) became the effective standard of care for metastatic RCC alongside immune checkpoint blockade (ICB). However, responses are heterogeneous & predictive biomarkers lacking. Tumor-associated macrophages (TAMs) correlate with poor survival & treatment resistance, yet TAM targeting in RCC remains unexplored due to limited preclinical models. Using a spontaneous ccRCC mouse model with Vhl, p53, & Rb1 deletions, we tested TAM depletion with a clinical-grade CSF1R inhibitor (CSF1Ri) combined with TKI or ICB, followed by scRNAseq profiling. Interestingly TAM depletion abolished ICB response by selectively depleting antigen-presenting TAMs, causing T cell exclusion, but had no impact on TKI response. Surprisingly, hypoxyprobe staining showed that both CSF1Ri & TKI induced severe intratumor hypoxia, enabling us to identify a true hypoxia-specific TAM subset distinct from VHL-loss pseudohypoxia. These TAMs predict poor ICB/TKI outcomes from pretreatment tumors & tracked with treatment-induced necrosis in post-treatment tumors. Notably, TKI exacerbated metastases in novel metastatic syngeneic RCC models, cautioning against hypoxia-inducing agents in such tumors. Our findings highlight mechanistic insights into the failure of CSF1Ri trials, hypoxia-driven resistance, & the need for mechanism-guided biomarkers. Funding Sources National Cancer Institute R01 CA258886 Department of Defense Kidney Cancer Research Program KC180165/W81XWH1910792 Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)