期刊
CANCER CELL
卷 39, 期 5, 页码 649-+出版社
CELL PRESS
DOI: 10.1016/j.ccell.2021.02.015
关键词
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资金
- National Institutes of Health [U01 CA233100, R01 CA227388, U2C CA233195, T32 GM008313, T32 CA009172]
- National Science Foundation [GRFP DGE1144152]
- Novartis-DDP grant
- Kure It-AACR grant
- Dunkin' Donuts Breakthrough Grant
- DOD CDMRP [KC170216, KC190130]
- DOD Academy of Kidney Cancer Investigators [KC190128]
- Kohlberg Chair at Harvard Medical School
- Trust Family, Michael Brigham, and Loker Pinard Funds for Kidney Cancer Research at DFCI
- DF/HCC Kidney Cancer SPORE [P50CA101942-15]
- CDMRP [1100819, KC170216] Funding Source: Federal RePORTER
The study shows that immune checkpoint blockade (ICB) remodels the RCC microenvironment and modifies the interplay between cancer and immune cell populations, critical for understanding response and resistance to ICB.
Immune checkpoint blockade (ICB) results in durable disease control in a subset of patients with advanced renal cell carcinoma (RCC), but mechanisms driving resistance are poorly understood. We characterize the single-cell transcriptomes of cancer and immune cells from metastatic RCC patients before or after ICB exposure. In responders, subsets of cytotoxic T cells express higher levels of co-inhibitory receptors and effector molecules. Macrophages from treated biopsies shift toward pro-inflammatory states in response to an interferon-rich microenvironment but also upregulate immunosuppressive markers. In cancer cells, we identify bifurcation into two subpopulations differing in angiogenic signaling and upregulation of immunosuppressive programs after ICB. Expression signatures for cancer cell subpopulations and immune evasion are associated with PBRM1 mutation and survival in primary and ICB-treated advanced RCC. Our findings demonstrate that ICB remodels the RCC microenvironment and modifies the interplay between cancer and immune cell populations critical for understanding response and resistance to ICB.
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