R01AI166598

Uncovering the Metabolic Underpinnings of T Cell Exhaustion - Project Summary/Abstract

The successes of immunotherapies like blockade of co-inhibitory "checkpoint" molecules have changed the treatment paradigm of cancer. However, the fact that robust responses are restricted to a subset of patients highlights the need to further understand the biology of exhausted T cells: what drives their differentiation, maintains their dysfunction, and how they may be reinvigorated to eradicate tumor cells.

Our lab and others have revealed that metabolic stress and mitochondrial dysfunction are key drivers in T cell exhaustion, both from a cell extrinsic and cell intrinsic perspective. We recently reported that mitochondrial stress and reactive oxygen species (ROS) production, driven to intolerable levels under hypoxic environments in the face of persistent antigen, was sufficient to deviate cells into a terminally exhausted fate. Antioxidants both pharmacologic and genetic could bias T cell differentiation away from exhaustion to more functional fates. But precisely how ROS production alters T cell fate and function remains unclear.

One of the more intriguing observations was elevating ROS via mitochondrial dysfunction altered T cell signaling: as peroxide is one of the more potent inhibitors of tyrosine phosphatases, elevating ROS alone mimicked TCR and other phosphotyrosine signals. ROS also dramatically reprograms cellular metabolism: by inhibiting aconitase, citrate is driven from the mitochondria where it is converted to acetyl-CoA, acting as a substrate for de novo lipogenesis. As a result, while exhausted cells possess dysfunctional mitochondria and compete poorly for glucose, they are loaded with lipid droplets and repress fatty acid oxidation and lipolysis.

While we know that mitochondrial stress can drive T cells to exhaustion and that terminally exhausted T cells are metabolically insufficient, the mechanisms that ultimately drive and enforce the phenotype remain unclear. In this proposal, we will identify the metabolic underpinnings of T cell exhaustion: how metabolic stress can interfere with signaling, transcription, and differentiation.

Aim 1: Determine how oxidative stress alters T cell signaling cascades at the level of phosphatase inhibition. ROS play central roles in signaling as inhibitors of tyrosine phosphatases. We will determine the role of ROS in exhausted T cell function in vivo, and use proteomics and transcriptomic technologies to identify the phosphorylation cascades susceptible to ROS induction.

Aim 2: Identify how ROS-mediated changes in metabolic flux undermine T cell function. In this aim, we will explore the role increased lipid storage plays in T cell function and ask whether these elevated levels of lipids represent "dead weight" or an untapped fuel source.

Aim 3: Define the importance of altered nutrient pathways induced through oxidative stress responses. Our data suggest SLC16A11 similarly supports lactate uptake into exhausted T cells and maintains their dysfunctional state. Using a conditional knockout mouse and blocking antibodies, we will determine the importance of monocarboxylate metabolism in exhausted T cell biology.

University Of Pittsburgh - Of The Commonwealth System Of Higher Education

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS, TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Pittsburgh, Pennsylvania 152221808 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 404% from $633,550 to $3,195,086.