34Hypoxia and immune suppression shapes therapeutic outcomes and metastases in clear cell renal cell carcinoma

Abstract Background Vascular endothelial growth factor receptor-targeting tyrosine kinase inhibitors (VEGFR-TKIs) and aPD1 combinations are effective in multiple solid tumors, particularly in clear cell renal cell carcinoma (ccRCC), due to its characteristic pseudo-hypoxic, hyper-angiogenic state dr...

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Published in:The oncologist (Dayton, Ohio) Vol. 30; no. Supplement_2
Main Authors: Vuong, Lynda, Cornish, Andrew, Khandwala, Yash, Jiang, Hui, Mascareno, Eduardo, Zheng, Doris, Rappold, Phillip, Leibold, Josef, Sabio, Erich, Weiss, Kate, Gonzalez, Carlene, Rittenhouse, Nicole, Ji, Liangliang, Zhang, Jing, Adlesic, Mojca, Akin, Oguz, Flynn, Jessica, Krishna, Chirag, Sanchez, Alejandro, Natale, Renzo Di, Blum, Kyle, Russo, Paul, Coleman, Jonathan, Frew, Ian, Chowell, Diego, Chen, Yingbei, Solit, David, Ostrovnaya, Irina, Motzer, Robert, Voss, Martin, Kotecha, Ritesh, Chan, Timothy, Kuo, Fengshen, Li, Ming, Hakimi, A Ari
Format: Journal Article
Language:English
Published: Oxford University Press 01.10.2025
Subjects:
hypoxia
tumor associated macrophages
immune checkpoint blockade
ISSN:1083-7159, 1549-490X
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Summary:Abstract Background Vascular endothelial growth factor receptor-targeting tyrosine kinase inhibitors (VEGFR-TKIs) and aPD1 combinations are effective in multiple solid tumors, particularly in clear cell renal cell carcinoma (ccRCC), due to its characteristic pseudo-hypoxic, hyper-angiogenic state driven by biallelic VHL-loss. However, long-term durability is inferior to dual aPD1/aCTLA4 regimens, yet the mechanisms underlying these differences remain unclear. Methods Since tumor-associated macrophages (TAMs) are implicated in therapeutic resistance, we used immunofluorescence staining and scRNAseq (n = 37) to investigate TAM evolution following VEGFR-TKI, aPD1 and combined VEGFR-TKI/aPD1 treatment in a genetically engineered (Ksp1.3cre-ERT2Vhlf/fp53f/f Rb1f/f) ccRCC mouse model. We further corroborate our findings in a novel human scRNAseq cohort (n = 15) of on-treatment tumor samples from patients who received VEGFR-TKI/aPD1 or aPD1/aCTLA4 therapies and experienced a range of clinical responses before undergoing cytoreductive nephrectomy. Results By quantifying hypoxia using pimonidazole in mice, we reveal that VEGFR-TKIs induced severe intratumor hypoxia. This enabled the identification of hypoxia-responsive SPP1+ TAMs that are absent in baseline pseudo-hypoxic ccRCC tumors. This proxy of true hypoxia tracks with successful response to VEGFR-TKI/aPD1 in both mouse and human on-treatment samples, reflecting treatment-induced hypoxic necrosis. Paradoxically, high levels of pretreatment hypoxic TAM signatures predicted worse outcomes across multiple VEGFR-TKI/aPD1 trials including JAVELIN101 and IMMOTION150/151, as well as an MSKCC real-world data cohort (n = 44). Furthermore, extended exposure to hypoxia-inducing VEGFR-TKIs and aPD1 exacerbated metastasis in two syngeneic models of ccRCC. Conclusions In conclusion, our study suggests that VEGFR-TKIs induce tumor hypoxia in responsive ccRCC tumors, but preexisting hypoxia renders tumors refractory to VEGFR-TKI/aPD1 therapies. Our data also suggests that chronic therapy-induced hypoxia and inflammation may promote metastatic evolution, thus offering potential mechanistic insight into the poor durability of VEGFR-TKI/aPD1 regimens across multiple cancer types.
ISSN:1083-7159
1549-490X
DOI:10.1093/oncolo/oyaf276.035