| Autor: |
A. Ari Hakimi, Martin H. Voss, Robert J. Motzer, Timothy A. Chan, Scott W. Lowe, David B. Solit, Ming O. Li, Diego Chowell, Xiaoxiao Ma, Kyle A. Blum, Renzo G. DiNatale, Vladimir Makarov, Irina Ostrovnaya, Brandon J. Manley, Ed Reznik, Jonathan Coleman, Paul Russo, Ying-Bei Chen, John Millholland, Alexander Savchenko, Albert Reising, Mahtab Marker, Mahdi Golkaram, Eduardo A. Mascareno, Andrew W. Silagy, Anders E. Berglund, Ming Liu, Briana G. Nixon, Hui Jiang, Erich Sabio, Fengshen Kuo, Michael Curry, Nicholas H. Chakiryan, Josef Leibold, Lynda Vuong, Phillip M. Rappold |
| Rok vydání: |
2023 |
| ISSN: |
2159-8290 |
| Popis: |
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 |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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