A Targetable Myeloid Inflammatory State Governs Disease Recurrence in Clear-Cell Renal Cell Carcinoma

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, Eduardo A. Mascareno, Mahdi Golkaram, Mahtab Marker, Albert Reising, Alexander Savchenko, John Millholland, Ying Bei Chen, Paul RussoJonathan 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

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

It is poorly understood how the tumor immune microenvironment influences disease recurrence in localized clear-cell renal cell carcinoma (ccRCC). Here we per-formed 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 identified myeloid-derived IL6 as a key mediator. Furthermore, a novel myeloid gene signature strongly correlated with disease recurrence and overall survival on uni-and multivariate analyses and is linked to TP53 inactivation across multiple data sets. Strikingly, effector T-cell gene signatures, infiltration pat-terns, and exhaustion markers were not associated with disease recurrence. Targeting immunosuppres-sive myeloid inflammation with an adenosine A2A receptor antagonist in a novel, immunocompetent, Tp53-inactivated mouse model significantly reduced metastatic development. Our findings suggest that myeloid inflammation promotes disease recurrence in ccRCC and is targetable as well as provide a potential biomarker-based framework for the design of future immuno-oncology trials in ccRCC. SIGNIFICANCE: Improved understanding of factors that influence metastatic development in localized ccRCC is greatly needed to aid accurate prediction of disease recurrence, clinical decision-making, and future adjuvant clinical trial design. Our analysis implicates intratumoral myeloid inflammation as a key driver of metastasis in patients and a novel immunocompetent mouse model.

Original languageEnglish
Pages (from-to)2308-2329
Number of pages22
JournalCancer Discovery
Volume12
Issue number10
DOIs
StatePublished - 1 Oct 2022

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