It is poorly understood how the tumor immune microenvironment influences disease recurrence in localized clear cell renal cell carcinoma (ccRCC). Here we perform whole-transcriptomic profiling of 236 tumors from patients assigned to the placebo-only arm of a randomized, adjuvant clinical trial for high-risk localized ccRCC. Unbiased pathway analysis identifies myeloid-derived interleukin-6 (IL-6) as a key mediator. Furthermore, a novel myeloid gene signature strongly correlates with disease recurrence and overall survival on uni- and multivariate analysis and is linked to TP53 inactivation across multiple datasets. Strikingly, effector T cell gene signatures, infiltration patterns, and exhaustion markers were not associated with disease recurrence. Targeting immunosuppressive myeloid inflammation with an adenosine A2A receptor antagonist in a novel, immunocompetent, Tp53-inactivated mouse model significantly reduces metastatic development. Our findings suggest myeloid inflammation promotes disease recurrence in ccRCC, is targetable, and provide a potential biomarker-based framework for the design of future immuno-oncology trials in ccRCC.
Cancer discovery. 2022 Jun 27 [Epub ahead of print]
Phillip M Rappold, Lynda Vuong, Josef Leibold, Nicholas H Chakiryan, Michael Curry, Fengshen Kuo, Erich Sabio, Hui Jiang, Briana G Nixon, Ming Liu, Anders E Berglund, Andrew W Silagy, Ankur Mascareno, Mahdi Golkaram, Mahtab Marker, Albert Reising, Alexander Savchenko, John M Millholland, Ying-Bei Chen, Paul Russo, Jonathan Coleman, Ed Reznik, Brandon J Manley, Irina Ostrovnaya, Vladimir Makarov, Renzo G DiNatale, Kyle A Blum, Xiaoxiao Ma, Diego Chowell, Ming O Li, David B Solit, Scott W Lowe, Timothy A Chan, Robert J Motzer, Martin H Voss, A Ari Hakimi
Memorial Sloan Kettering Cancer Center, New York, NY, United States., MSKCC, New York, New York, United States., Memorial Sloan Kettering Cancer Center, New York, New York, United States., Moffitt Cancer Center, Tampa, United States., Memorial Sloan Kettering Cancer Center, New York, United States., Legend Biotech USA, NJ, United States., H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States., Memorial Sloan Kettering Cancer Center, East Northport, NY, Armenia., Illumina Inc., San Diego, United States., Novartis Oncology, East Hanover, New Jersey, United States., Oncology Precision Medicine, Novartis, Cambridge, MA, United States., Novartis Institutes of Biomedical Research, Cambridge, United States., Memorial Sloan Kettering, New York, NY, United States., Memorial Sloan Kettering Cancer Center, Cleveland, OH, United States., Memorial Sloan Kettering Cancer Center, New York City, NY, United States., Cleveland Clinic, Cleveland, United States., Icahn School of Medicine at Mount Sinai, New York, NY, United States., Cleveland Clinic, Cleveland, OH, United States.