Dysfunction of exhausted T cells is enforced by MCT11-mediated lactate metabolism
CD8<sup>+</sup> T cells are critical mediators of antitumor immunity but differentiate into a dysfunctional state, known as T cell exhaustion, after persistent T cell receptor stimulation in the tumor microenvironment (TME). Exhausted T (T<sub>ex</sub>) cells are characterized by upregulation of coinhibitory molecules and reduced polyfunctionality. T cells in the TME experience an immunosuppressive metabolic environment via reduced levels of nutrients and oxygen and a buildup of lactic acid. Here we show that terminally T<sub>ex</sub> cells uniquely upregulate Slc16a11, which encodes monocarboxylate transporter 11 (MCT11). Conditional deletion of MCT11 in T cells reduced lactic acid uptake by T<sub>ex</sub> cells and improved their effector function. Targeting MCT11 with an antibody reduced lactate uptake specifically in T<sub>ex</sub> cells, which, when used therapeutically in tumor-bearing mice, resulted in reduced tumor growth. These data support a model in which T<sub>ex</sub> cells upregulate MCT11, rendering them sensitive to lactic acid present at high levels in the TME.
Authors
- B. Rhodes Ford (ORCID: https://orcid.org/0000-0001-8777-5244)
- Andrew Frisch (ORCID: https://orcid.org/0000-0002-0080-9147)
- Bingxian Xie (ORCID: https://orcid.org/0000-0001-9816-2670)
- Dayana B. Rivadeneira (ORCID: https://orcid.org/0000-0001-9483-7036)
- Amanda C. Poholek (ORCID: https://orcid.org/0000-0002-5587-8940)
- Victoria Dean (ORCID: https://orcid.org/0009-0002-9136-3917)
- Konstantinos Lontos (ORCID: https://orcid.org/0000-0003-0216-3818)
- Ronal M. Peralta (ORCID: https://orcid.org/0000-0002-2863-0157)
- Larry Kane (ORCID: https://orcid.org/0000-0001-5198-516X)
- Supriya Joshi (ORCID: https://orcid.org/0000-0002-5205-3847)
- Kevin Quann (ORCID: https://orcid.org/0000-0003-2213-3771)
- Hector Nieves-Rosado (ORCID: https://orcid.org/0000-0001-8084-0728)
- Mary Philbin
- Sébastien Gingras (ORCID: https://orcid.org/0000-0003-2607-8642)
- Kellie Spahr (ORCID: https://orcid.org/0000-0002-4119-4994)
- Greg M. Delgoffe (ORCID: https://orcid.org/0000-0002-2957-8135)
- Anthony R. Cillo (ORCID: https://orcid.org/0000-0002-3213-3129)
Institutions
- University of Pittsburgh (US)
- UPMC Hillman Cancer Center (US)
Publication Details
- Journal
- Nature Immunology
- Published
- 2024-11-08
- DOI
- https://doi.org/10.1038/s41590-024-01999-3
- Citations
- 116
- Primary Topic
- Immune Cell Function and Interaction
- Type
- article
- Field-Weighted Citation Impact
- 27.90
Funders
- Cancer Research Institute
- National Institutes of Health
- Stand Up To Cancer
- National Cancer Institute
- National Institute of Allergy and Infectious Diseases