# Lactate transporter MCT1 is required for the high suppressive function of tumor infiltrating regulatory T cells

> **NIH NIH F31** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $40,654

## Abstract

Lactate transporter MCT1 is required for the high suppressive function of tumor infiltrating regulatory T cells
Abstract
 Cancer immunotherapy has revolutionized the way we treat cancer, but most patients fail to respond due
to several resistance mechanisms including the recruitment, proliferation, and differentiation of regulatory T (Treg)
cells in the tumor microenvironment (TME). While cytotoxic effector T (Teff) cells are rendered dysfunctional by
the TME, the natural immunosuppressive function of Treg cells remains intact. Treg and Teff cells exhibit distinct
metabolisms which may explain the discrepancy in their function within the TME. Metabolically, the TME is
characterized by hypoxia, low pH, and limiting metabolites such as glucose and amino acids. While the highly
glycolytic Teff cells are in direct competition with the tumor for glucose, recent evidence suggests Foxp3, the
lineage defining transcription factor of Treg cells, can reprogram metabolism of Treg cells to function in high lactate,
low glucose environments. Hypothesizing that Treg cells were supported by lactic acid within the TME, we bred
a mouse with a Treg specific deletion of the lactate transporter MCT1 (Slc16a1f/f Foxp3YFPCre) and inoculated
them with B16 melanoma. Treg specific loss of MCT1 resulted in slowed tumor growth and increased survival
without leading to systemic autoimmunity. Measuring lactic acid concentration, we observed high levels within
B16 tumors relative to peripheral lymphoid tissues. While MCT1 is predominantly recognized to transport lactate,
it has several other substrates, such as propionate and studies on colonic Treg cells suggest propionate enhances
Treg cell function and differentiation. Preliminary data from our lab corroborate these results, showing Treg cells
conditioned in propionate increased expression of Treg markers Nrp1 and Helios. However, from these
observations two questions arise, 1) is MCT1 required for Treg cell function only in lactate high TMEs, and 2) how
do non-lactate MCT1 substrates influence Treg cell metabolism? We hypothesize that MCT1 is required for
intratumoral Treg cell function in lactate rich TMEs and that its substrates promote an oxidative
metabolism and the expression of Treg cell signature genes. To address this hypothesis, first we will (1)
determine the requirement of MCT1 for intratumoral Treg cell function in metabolically distinct TMEs. We will
inoculate Slc16a1f/f Foxp3YFPCre mice with metabolically distinct melanoma cell lines and measure the impact
on intratumoral Treg cell metabolism via Seahorse, and function via suppression assay. Second, we will (2)
determine the impact of non-lactate MCT1 substrate propionate on Treg cell metabolism. Using Foxp3YFPCre
mice we will isolate Treg cells then condition them in media containing propionate and measure the impact on
metabolism via Seahorse and apply isotopic flux analysis to identifying how Treg cells utilize propionate. By
understanding the role of MCT...

## Key facts

- **NIH application ID:** 10199740
- **Project number:** 5F31AI149971-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** McLane Watson
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $40,654
- **Award type:** 5
- **Project period:** 2020-02-01 → 2021-11-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10199740

## Citation

> US National Institutes of Health, RePORTER application 10199740, Lactate transporter MCT1 is required for the high suppressive function of tumor infiltrating regulatory T cells (5F31AI149971-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10199740. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*