R01AI187349

TLE transcription cofactors in anti-viral and anti-tumor immunity - CD8+ T lymphocytes are essential players in mounting protective cellular immune responses against pathogens and malignantly transformed cells.

However, exposure to persisting antigens due to chronic viral infections or tumor microenvironment drives CD8+ T cells into an exhausted/hypofunctional state, limiting the efficacy of immunotherapy.

There is an urgent need to molecularly reconstruct the exhaustion process and identify actionable therapeutic targets to alleviate exhaustion and restore durable functions in T cells.

Transcriptional and epigenetic regulation has essential roles in initiation, fate decision, differentiation, and stability of the exhausted CD8+ T (TEX) cells.

Transcription cofactors do not bind DNA directly, but have the unique ability of interacting with multiple sequence-specific transcription factors (TFs) and form integrative regulatory complexes.

Our preliminary studies on TLE3 cofactor revealed its distinct impact on TEX cells elicited by chronic viral infection.

We hypothesize that TLE3 forges a critical linker that integrates TFs and epigenetic regulators and controls TEX functions via distinct regulatory complexes.

Ectopic expression of an engineered human TLE3 variant that lacked the C-terminal WDR domain (called TLE3-DWDR) in HCD19-CAR-T cells enhanced their anti-leukemia capacity in a xenograft model.

We further hypothesize that molecular engineering of TLE3 decouples its 'preferred' regulatory effects from the 'unwanted' ones and can be leveraged to enhance CAR-T cells in tumor control.

We will test these through two aims:

Aim 1, to dissect TLE3-mediated complex assembly in directing TEX cell fate and persistence.

We will use target gene-specific and genome-wide approaches to dissect the assembly of TLE3-nucleated complexes, including 1) TLE3 recruitment by TFs mobilized by persistent antigen stimulation, 2) TF-TLE3 cooperativity in engaging MLL4 to deploy H3K4ME1/2 for enhancer initialization, 3) TF-TLE3 cooperativity in engaging HDAC1 and/or EZH2 for enhancer inactivation, and 4) essential requirements for TLE3 in stabilizing the TF-epigenetic regulator complexes.

Aim 2, to expand the reprogramming capacity by engineered human TLE3 to enhance CAR-T cells.

We will pursue the following goals: 1) to test if the beneficial effects of TLE3-DWDR are broadly applicable to different CAR binders, resulting in improved controls over leukemia relapse and solid tumors, 2) to investigate the mechanisms underlying TLE3-DWDR-mediated reprogramming: reshaping existing TLE3-nucleated complexes and/or acquiring de novo complexes, and 3) to refine TLE3 engineering via domain and contact surface optimization to boost CAR-T effector functions.

These efforts will not only improve the understanding of the T cell exhaustion process with increased precision and resolution, but also establish TLE3 functional decoupling as an actionable strategy to avert T cell exhaustion and achieve durable immune control over chronic infections and cancers.

HMH Hospitals Corporation

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]

New Jersey United States

State-Wide

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