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Metabolic support of regulatory T cells by lactic acid

Watson, McLane J and Vignali, Paolo DA and Mullett, Steven J and Overacre, Abigail E and Peralta, Ronal M and Grebinoski, Stephanie and Menk, Ashley V and Rittenhouse, Natalie L and DePeaux, Kristin and Whetstone, Ryan and Vignali, Dario AA and Hand, Timothy W and Poholek, Amanda C and Morrison, Brett M and Rothstein, Jeffrey D and Wendell, Stacy G and Delgoffe, Greg M (2022) Metabolic support of regulatory T cells by lactic acid. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Regulatory T (Treg) cells, although vital for immune homeostasis, also represent a major barrier to anti-cancer immunity, as the tumor microenvironment (TME) promotes the recruitment, differentiation, and activity of these cells1,2. Tumor cells show deregulated metabolism, leading to a metabolite-depleted, hypoxic and acidic TME3, which places infiltrating effector T cells in competition with the tumor for metabolites and impairs their function4–6. At the same time, Treg cells maintain a strong suppression of effector T cells within the TME7,8. As previous studies suggested that Treg cells possess a distinct metabolic profile from effector T cells9–11, we hypothesized that the altered metabolic landscape of the TME and increased activity of intratumoral Treg cells are linked. Here we show that Treg cells display broad heterogeneity in their metabolism of glucose within normal and transformed tissues and can engage an alternative metabolic pathway to maintain suppressive function and proliferation. Glucose uptake correlates with poorer suppressive function and long-term instability, and high-glucose conditions impair the function and stability of Treg cells in vitro. Treg cells instead upregulate pathways involved in the metabolism of the glycolytic by-product lactic acid. Treg cells withstand high-lactate conditions, and treatment with lactate prevents the destabilizing effects of high-glucose conditions, generating intermediates necessary for proliferation. Lactic acid also contributes directly to epigenetic modifications through histone lactylation which may support the expression of Treg cell signature genes. Deletion of MCT1—a lactate transporter—in Treg cells reveals that lactate uptake is dispensable for the function of peripheral Treg cells but required intratumorally, resulting in slowed tumor growth and an increased response to immunotherapy. Thus, Treg cells are metabolically flexible: they can use ‘alternative’ metabolites in the TME to maintain their suppressive identity. Further, our results suggest that tumors avoid destruction by not only depriving effector T cells of nutrients, but also metabolically supporting regulatory populations.

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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Watson, McLane Jmcw56@pitt.edumcw56
Vignali, Paolo DApdv7@pitt.edupdv7
Mullett, Steven Jsjmst52@pitt.edusjmst52
Overacre, Abigail Eoveracre@pitt.eduOVERACRE
Peralta, Ronal Mrmp81@pitt.edurpm81
Grebinoski, Stephaniesjg83@pitt.edusjg83
Menk, Ashley Vmenka@upmc.edu
Rittenhouse, Natalie Lnnlr23@pitt.edunlr23
DePeaux, Kristinkrd61@pitt.edukrd61
Whetstone, Ryanrdw16@pitt.eduRDW16
Vignali, Dario AAdvignali@pitt.eduDVIGNALI
Hand, Timothy Wtimothy.hand@chp.edu
Poholek, Amanda Cpoholeka@pitt.edupoholeka
Morrison, Brett Mbmorris7@jhmi.edu
Rothstein, Jeffrey Djrothstein@jhmi.edu
Wendell, Stacy Ggstacy@pitt.edugstacy
Delgoffe, Greg Mgdelgoffe@pitt.eduGMD34
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairTurnquist, Heth Rhet5@pitt.eduhet5
Thesis AdvisorDelgoffe, Greg Mgdelgoffe@pitt.edugdelgoffe
Committee MemberVignali, Dario AAdvignali@pitt.edudvignali
Committee MemberPoholek, Amanda Cpoholeka@pitt.edupoholeka
Committee MemberWendell, Stacy Ggstacy@pitt.edugstacy
Date: 1 January 2022
Date Type: Publication
Defense Date: 26 October 2021
Approval Date: 1 January 2022
Submission Date: 19 November 2021
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 124
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Microbiology and Immunology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: regulatory T cells, tumor microenvironment, cancer, immunotherapy, metabolism, immunometabolism, Treg, lactic acid, glucose
Date Deposited: 01 Jan 2022 20:07
Last Modified: 01 Jan 2022 20:07
URI: http://d-scholarship.pitt.edu/id/eprint/41961

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