Peralta, Ronal
(2024)
Role of lactate metabolism in T cell activation and exhaustion.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
CD8+ T cells are critical mediators of immunity against infected and malignant cells, but differentiate into a state of dysfunction, known as exhaustion, after experiencing persistent TCR stimulation and metabolic stress in the tumor microenvironment (TME). Exhausted T (Texh) cells are characterized by the sustained upregulation of co-inhibitory molecules and reduced stemness and polyfunctionality. The TME creates an immunosuppressive metabolic environment via reduced levels of vital nutrients and oxygen, combined with increased catabolic waste products. Additionally, highly glycolytic tumor and stromal cells secrete lactic acid, which acidifies the extracellular space. T cells have high metabolic plasticity and have been shown to metabolize lactate. Here we investigate the role of lactic acid metabolism during T cell synapse formation and lactic acid metabolism in Texh cells infiltrating tumors. We found that during T cell activation, T cells restrict aerobic glycolysis to the T cell synapse. Additionally, we found that LDH bound the transcripts of many effector and metabolic genes in naïve T cells. Furthermore, we investigated the lactic acid metabolism of tumor infiltrating Texh cells. We found that Texh cells upregulate a newly characterized monocarboxylate transporter, MCT11 (encoded by Slc16a11), enabling uptake of lactic acid which can drive their dysfunction. MCT11 expression requires both the core exhaustion transcriptional program induced through chronic activation and metabolic stress signals, like hypoxia, originating within tissues. While overexpression of MCT11 in tumor- specific T cells decreased their polyfunctionality, conditional deletion of MCT11 in T cells reduced lactic acid uptake in Texh cells and improved effector function and response to immunotherapy. Further, a monoclonal antibody targeting MCT11 reduced lactate uptake
specifically in Texh cells, which, when used therapeutically in tumor-bearing mice, resulted in significantly reduced tumor growth, inducing complete regressions and immunologic memory in lactate-rich tumors. Our data support a model in which the exhaustion program upregulates MCT11, rendering exhausted T cells sensitive to toxic lactic acid present at high levels in the tumor microenvironment. MCT11 represents an attractive target to edit in therapeutic T cells or block using antibodies to render exhausted T cells impervious to lactic acid, allowing for tumor eradication.
Share
| Citation/Export: |
|
| Social Networking: |
|
Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
|
| Date: |
14 October 2024 |
| Date Type: |
Publication |
| Defense Date: |
22 July 2024 |
| Approval Date: |
14 October 2024 |
| Submission Date: |
3 August 2024 |
| Access Restriction: |
1 year -- Restrict access to University of Pittsburgh for a period of 1 year. |
| Number of Pages: |
123 |
| 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: |
T cell
Metabolism
Immuno-oncology |
| Date Deposited: |
14 Oct 2024 15:52 |
| Last Modified: |
14 Oct 2024 15:52 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/46823 |
Metrics
Monthly Views for the past 3 years
Plum Analytics
Actions (login required)
 |
View Item |
![[img]](https://d-scholarship.pitt.edu/style/images/fileicons/application_pdf.png)
![[feed]](/images/feed-icon-32x32.png){kind=icon}