期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 215, 期 4, 页码 1091-1100出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20171068
关键词
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资金
- Sidney Kimmel Foundation for Cancer Research [SKF-015-036]
- Stand Up To Cancer-American Association for Cancer Research [SU2C-AACR-IRG-04-16]
- National Institutes of Health Director's New Innovator Award [DP2AI136598]
- Cancer Institute, University of Pittsburgh Melanoma and Head and Neck Cancer SPO REs [T32 CA082084, F99CA222711]
- [P30CA047904]
Despite remarkable responses to cancer immunotherapy in a subset of patients, many patients remain resistant to these therapies. The tumor microenvironment can impose metabolic restrictions on T cell function, creating a resistance mechanism to immunotherapy. We have previously shown tumor-infiltrating T cells succumb to progressive loss of metabolic sufficiency, characterized by repression of mitochondrial activity that cannot be rescued by PD-1 blockade. 4-1BB, a costimulatory molecule highly expressed on exhausted T cells, has been shown to influence metabolic function. We hypothesized that 4-1BB signaling might provide metabolic support to tumor-infiltrating T cells. 4-1BB costimulation of CD8(+) T cells results in enhanced mitochondrial capacity (suggestive of fusion) and engages PGC1 alpha-mediated pathways via activation of p38-MAPK. 4-1BB treatment of mice improves metabolic sufficiency in endogenous and adoptive therapeutic CD8(+) T cells. 4-1BB stimulation combined with PD-1 blockade results in robust antitumor immunity. Sequenced studies revealed the metabolic support afforded by 4-1BB agonism need not be continuous and that a short course of anti-4-1BB pretreatment was sufficient to provide a synergistic response. Our studies highlight metabolic reprogramming as the dominant effect of 4-1BB therapy and suggest that combinatorial strategies using 4-1BB agonism may help overcome the immunosuppressive metabolic landscape of the tumor microenvironment.
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