Immunometabolic coevolution defines unique microenvironmental niches in ccRCC
Cerise Tang, Amy Xie, Eric Minwei Liu, Fengshen Kuo, Min‐Soo Kim, Renzo G. DiNatale, Mahdi Golkaram, Ying‐Bei Chen, Sounak Gupta, Robert J. Motzer, Paul Russo, Jonathan Coleman, Maria I. Carlo, Martin H. Voss, Ritesh R. Kotecha, Chung‐Han Lee, Wesley Tansey, Nikolaus Schultz, A. Ari Hakimi, Ed Reznik
Abstract
Tumor cell phenotypes and anti-tumor immune responses are shaped by local metabolite availability, but intratumoral metabolite heterogeneity (IMH) and its phenotypic consequences remain poorly understood. To study IMH, we profiled tumor/normal regions from clear cell renal cell carcinoma (ccRCC) patients. A common pattern of IMH transcended all patients, characterized by correlated fluctuations in the abundance of metabolites and processes associated with ferroptosis. Analysis of intratumoral metabolite-RNA covariation revealed that the immune composition of the microenvironment, especially the abundance of myeloid cells, drove intratumoral metabolite variation. Motivated by the strength of RNA-metabolite covariation and the clinical significance of RNA biomarkers in ccRCC, we inferred metabolomic profiles from the RNA sequencing data of ccRCC patients enrolled in 7 clinical trials, and we ultimately identifyied metabolite biomarkers associated with response to anti-angiogenic agents. Local metabolic phenotypes, therefore, emerge in tandem with the immune microenvironment, influence ongoing tumor evolution, and are associated with therapeutic sensitivity.