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

Rappold, Phillip M, Vuong, Lynda, Leibold, Josef, Chakiryan, Nicholas H, Curry, Michael, Kuo, Fengshen, Sabio, Erich, Jiang, Hui, Nixon, Briana G, Liu, Ming, Berglund, Anders E, Silagy, Andrew W, Mascareno, Eduardo A, Golkaram, Mahdi, Marker, Mahtab, Reising, Albert, Savchenko, Alexander, Millholland, John, Chen, Ying-Bei, Russo, Paul, Coleman, Jonathan, Reznik, Ed, Manley, Brandon J, Ostrovnaya, Irina, Makarov, Vladimir, DiNatale, Renzo G, Blum, Kyle A, Ma, Xiaoxiao, Chowell, Diego, Li, Ming O, Solit, David B, Lowe, Scott W, Chan, Timothy A, Motzer, Robert J, Voss, Martin H, Hakimi, A Ari (October 2022) A Targetable Myeloid Inflammatory State Governs Disease Recurrence in Clear-Cell Renal Cell Carcinoma. Cancer Discovery, 12 (10). pp. 2308-2329. ISSN 2159-8274

PDF A Targetable Myeloid Inflammatory State Governs Disease Recurrence in Clear-Cell Renal Cell Carcinoma.pdf - Published Version Available under License Creative Commons Attribution. Download (3MB)

Abstract

It is poorly understood how the tumor immune microenvironment influences disease recurrence in localized clear-cell renal cell carcinoma (ccRCC). Here we performed 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 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 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. This article is highlighted in the In This Issue feature, p. 2221.

Item Type:	Paper
Subjects:	diseases & disorders > cancer diseases & disorders diseases & disorders > neoplasms organism description > animal diseases & disorders > inflammation organs, tissues, organelles, cell types and functions > organs types and functions > kidney organism description > animal > mammal organism description > animal > mammal > rodent > mouse organs, tissues, organelles, cell types and functions > organs types and functions organs, tissues, organelles, cell types and functions diseases & disorders > cancer > prognosis organism description > animal > mammal > rodent
CSHL Authors:	Lowe, Scott W.
Communities:	CSHL labs > Lowe lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	5 October 2022
Date Deposited:	03 Oct 2023 20:22
Last Modified:	16 Jan 2024 21:30
PMCID:	PMC9720541
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/41117

Actions (login required)

Administrator's edit/view item