A targetable myeloid inflammatory state governs disease recurrence in clear-cell renal cell carcinoma Journal Article
| Authors: | Rappold, P. M.; Vuong, L.; Leibold, J.; Chakiryan, N. H.; Curry, M.; Kuo, F.; Sabio, E.; Jiang, H.; Nixon, B. G.; Liu, M.; Berglund, A. E.; Silagy, A. W.; Mascareno, E. A.; Golkaram, M.; Marker, M.; Reising, A.; Savchenko, A.; Millholland, J.; Chen, Y. B.; Russo, P.; Coleman, J.; Reznik, E.; Manley, B. J.; Ostrovnaya, I.; Makarov, V.; DiNatale, R. G.; Blum, K. A.; Ma, X.; Chowell, D.; Li, M. O.; Solit, D. B.; Lowe, S. W.; Chan, T. A.; Motzer, R. J.; Voss, M. H.; Hakimi, A. A. |
| Article Title: | A targetable myeloid inflammatory state governs disease recurrence in clear-cell renal cell carcinoma |
| 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. © 2022 American Association for Cancer Research. |
| Journal Title: | Cancer Discovery |
| Volume: | 12 |
| Issue: | 10 |
| ISSN: | 2159-8274 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2022-10-01 |
| Start Page: | 2308 |
| End Page: | 2329 |
| Language: | English |
| DOI: | 10.1158/2159-8290.Cd-21-0925 |
| PUBMED: | 35758895 |
| PROVIDER: | scopus |
| PMCID: | PMC9720541 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 November 2022 -- Source: Scopus |
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