期刊
CANCER CELL
卷 39, 期 4, 页码 480-+出版社
CELL PRESS
DOI: 10.1016/j.ccell.2020.12.023
关键词
-
资金
- United States National Institutes of Health (NIH)/National Cancer Institute (NCI) [CA248430, CA217648, CA123088, CA099985, CA193136, CA152470]
- NIH through the University of Michigan Rogel Cancer Center Support Grant [P30CA46592]
Immunotherapy can induce durable clinical responses in some cancer patients, but resistance poses a major challenge. The expression of tumor STC1 is correlated with immunotherapy efficacy and negatively associated with patient survival across different cancer types. This study suggests that tumor STC1 may inhibit APC phagocytosis and contribute to tumor immune evasion and immunotherapy resistance.
Immunotherapy induces durable clinical responses in a fraction of patients with cancer. However, therapeutic resistance poses a major challenge to current immunotherapies. Here, we identify that expression of tumor stanniocalcin 1 (STC1) correlates with immunotherapy efficacy and is negatively associated with patient survival across diverse cancer types. Gain- and loss-of-function experiments demonstrate that tumor STC1 supports tumor progression and enables tumor resistance to checkpoint blockade in murine tumor models. Mechanistically, tumor STC1 interacts with calreticulin (CRT), an eat-me'' signal, and minimizes CRT membrane exposure, thereby abrogating membrane CRT-directed phagocytosis by antigen-presenting cells (APCs), including macrophages and dendritic cells. Consequently, this impairs APC capacity of antigen presentation and T cell activation. Thus, tumor STC1 inhibits APC phagocytosis and contributes to tumor immune evasion and immunotherapy resistance. We suggest that STC1 is a previously unappreciated phagocytosis checkpoint and targeting STC1 and its interaction with CRT may sensitize to cancer immunotherapy.
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