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J Exp Med. 2018 Apr 2;215(4):1091-1100. doi: 10.1084/jem.20171068. Epub 2018 Mar 6.

4-1BB costimulation induces T cell mitochondrial function and biogenesis enabling cancer immunotherapeutic responses.

Author information

1
Tumor Microenvironment Center, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA.
2
Department of Immunology, University of Pittsburgh, Pittsburgh, PA.
3
Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA.
4
Tumor Microenvironment Center, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA gdelgoffe@pitt.edu.

Abstract

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 PGC1α-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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