This three-year, $3,024,000 project grant from the National Institutes of Health Trans-NIH Research Support program will fund research at Massachusetts General Hospital to understand the epigenetic mechanisms governing CD8 T cell fate decisions in tumor microenvironments. Using loss-of-function and gain-of-function approaches for enhancer editing, the researchers aim to identify how, when, and where CD8 T cell commitment occurs in vivo, initially focusing on exhausted CD8 T cells in melanoma and...
This $103,948 Project Grant award from the National Cancer Institute (CFDA 93.393 - Cancer Cause and Prevention Research) to the Sloan-Kettering Institute for Cancer Research supports research aimed at elucidating the mechanisms driving T-cell dysfunction within the tumor microenvironment. The research plan includes two main components: Predoctoral research (Aim 1) to investigate how local amino acid availability limits effector function in tumor-infiltrating T-cells, including profiling the...
This $674,996 Project Grant award from the National Cancer Institute (CFDA 93.396 - Cancer Biology Research) supports research by the Sanford Burnham Prebys Medical Discovery Institute (SBP) to determine if targeting the PSGL-1 checkpoint inhibitor can promote the development and/or maintenance of CD8+ T cells essential for anti-tumor responses to PD-1 immune checkpoint blockade (ICB) therapy. The key objectives are to evaluate if PSGL-1 blockade can generate or sustain tumor-specific...
This $693,880 Project Grant award from the National Cancer Institute's Cancer Treatment Research program (CFDA 93.395) supports the development of a novel cancer immunotherapy approach using engineered CD4+ T cells. The goal is to create CD4+ T cells that can target the tumor microenvironment and overcome resistance to current immune checkpoint inhibitor therapies. Key elements include: Identifying key molecules and immune cell targets of the engineered CD4+ T cells in preclinical cancer...
This R03 project grant, awarded by the National Center for Advancing Translational Sciences (NCATS) under CFDA Program 93.350, aims to comprehensively identify metabolic enzymes that control the generation of TCF1+ progenitor CD8+ T cells, which are critical for durable anti-tumor immune responses. The $169,500 award, spanning from September 1, 2024 to August 31, 2026, will fund two key research objectives: Identifying metabolic enzymes whose loss alters T cell differentiation and the TCF1+...
This federal Project Grant award, funded by the National Cancer Institute (CFDA 93.398 Cancer Research Manpower program), will support research to gain a comprehensive understanding of how adoptive T cell therapy (ACT) becomes dysfunctional within the tumor microenvironment of pancreatic cancer. The $169,344 award, running from 09/01/2024 to 08/31/2026, will leverage single-cell and spatial multi-omics analyses, computational modeling, and functional experiments to: 1) identify targetable T...
This $693,942 National Institutes of Health National Heart Lung and Blood Institute Project Grant funds research at Northwestern University aimed at elucidating epigenetic modifiers of regulatory T cell function following viral pneumonia. The goal is to establish causal links between DNA methyltransferase activity, the DNMT adapter UHRF1, and DNA hypermethylation signatures in regulatory T cells during aging and their impaired reparative function after severe viral pneumonia. Through three...
This Project Grant award from the National Cancer Institute (CFDA 93.398 Cancer Research Manpower) provides $239,991 to The Trustees of the University of Pennsylvania to conduct research aimed at deciphering and modulating chimeric antigen receptor (CAR) T cell persistence and overcoming CAR T cell exhaustion. The key products and services to be delivered under this award include: Development of novel split-engineered CRISPR/dCAS9-guided epigenome editors that can inducibly activate target...
This Project Grant award from the National Institutes of Health (NIH) under the Trans-NIH Research Support program (CFDA 93.310) provides $1,602,000.00 to The Children's Hospital of Philadelphia Research Institute to develop and optimize a new class of Epigenetic Reprogramming Factors (ERFs) that can target hundreds, thousands, or tens of thousands of DNA regions in a pathway-specific manner. The goal is to leverage this ERF technology to prevent or reverse epigenetic signatures associated...
This Project Grant award of $102,324, provided by the National Cancer Institute (CFDA 93.398 Cancer Research Manpower program), supports research at the Medical University of South Carolina (MUSC) to elucidate the impact of peroxisome biogenesis on adaptive immune responses, particularly within the tumor microenvironment and anti-tumor immunity. The overarching goal is to understand how enhancing peroxisome capacity in T cells can improve their persistence and mitigate exhaustion when exposed to...
EPIGENETIC REGULATION OF EXHAUSTED CD8 T CELLS VIA THE MIR-29A-TET2 AXIS - CHRONIC INFECTIONS AND CANCER CAUSE CD8 T CELL EXHAUSTION, A DIFFERENTIATION STATE CHARACTERIZED BY THE INABILITY OF CD8 T CELLS TO PROVIDE IMMUNOLOGICAL PROTECTION. IMPROVING THE FUNCTION OF EXHAUSTED T CELLS (TEX) BY ANTAGONIZING CHECKPOINT INHIBITORS IS A POTENT IMMUNOTHERAPEUTIC STRATEGY. HOWEVER, MOST PATIENTS DO NOT EXHIBIT LONG-TERM PROTECTION, CREATING A NEED FOR IMPROVED IMMUNOTHERAPEUTIC STRATEGIES. RESISTANCE TO IMMUNOTHERAPY IS MAINLY ATTRIBUTED TO THE INABILITY OF CHECKPOINT INHIBITORS TO REVERSE THE TEX EPIGENOME. THEREFORE, EPIGENETICALLY RE-DIRECTING TEX DIFFERENTIATION TO INDUCE DURABLE RESPONSES IS KEY TO OVERCOMING RESISTANCE TO IMMUNOTHERAPY. TO DATE, MODIFYING A SINGLE TRANSCRIPTIONAL PATHWAY HAS HAD LIMITED SUCCESS IN PROVIDING FULL TEX REINVIGORATION AND INDUCING LONG-TERM PERSISTING IMMUNE RESPONSES. INSTEAD, MICRORNAS (MIRS) CAN HAVE A PROFOUND IMPACT ON THE EPIGENETIC REGULATION OF IMMUNE CELLS; HOWEVER, THE ROLE OF MIRS IN TEX DIFFERENTIATION IS UNDERSTUDIED. WE RECENTLY IDENTIFIED MIR-29A AS A UNIQUE MEMORY-ASSOCIATED MIR THAT IS REPRESSED IN TEX. WE DEMONSTRATED THAT ECTOPIC EXPRESSION OF MIR-29A ENHANCES TEX PERSISTENCE, ATTENUATES THEIR EXHAUSTION, AND PROMOTES DIFFERENTIATION OF A TEX SUBSET WITH PROGENITOR, STEM-LIKE CHARACTERISTICS THAT RESPONDS TO IMMUNOTHERAPY. IMPORTANTLY, OUR PRELIMINARY DATA SUGGEST THAT MIR-29A ALTERS THE EPIGENETIC PROFILE OF TEX AND PROMOTES DURABLE CD8 T CELL RESPONSES, IN STRIKING CONTRAST TO ANTI-PD-L1 THERAPY. MECHANISTICALLY, WE DEMONSTRATE THAT MIR-29A DIRECTLY TARGETS THE KEY DNA DEMETHYLATING ENZYME TET2 AND THAT TET2 OVEREXPRESSION ABROGATES KEY EFFECTS OF MIR-29A IN TEX DIFFERENTIATION. HOWEVER, THE MOLECULAR CIRCUITS INVOLVING MIR-29A AND TET2 AND THE IMPLICATION OF MIR-29A-TET2 AXIS IN CHECKPOINT INHIBITOR THERAPY IS UNKNOWN. THE GOAL OF THIS PROPOSAL IS TO UNCOVER THE ROLE OF MIR-29A IN TARGETING THE KEY EPIGENETIC MODULATOR TET2 AND, THUS, DEFINE THE ROLE OF MIR-29A IN SYNERGIZING WITH CHECKPOINT INHIBITORS. OUR CENTRAL HYPOTHESIS IS THAT MIR-29A REGULATES DNA METHYLATION BY DIRECTLY TARGETING TET2, THEREFORE, SYNERGIZES WITH CHECKPOINT INHIBITORS TO RE-DIRECT TEX DIFFERENTIATION. AIM 1. IDENTIFY THE ROLE OF THE MIR-29A-TET2 AXIS IN REGULATING TEX DIFFERENTIATION. WE HYPOTHESIZE THAT MIR- 29A REGULATES DNA DEMETHYLATION, BY DIRECTLY TARGETING TET2, THEREBY FUNDAMENTALLY ALTERS TEX DIFFERENTIATION. WE WILL ELUCIDATE THE TET2-DEPENDENT VERSUS TET2-INDEPENDENT EFFECTS OF MIR-29A IN TEX DIFFERENTIATION AND THE DOWNSTREAM EFFECTS IN DNA METHYLATION. AIM 2. IDENTIFY THE PATHWAYS BY WHICH MIR-29A SYNERGIZES WITH ANTI-PD-L1. WE HYPOTHESIZE THAT MIR-29A EPIGENETICALLY ALTERS THE DIFFERENTIATION OF THE PROGENITOR TEX SUBSET AND, THEREBY, SYNERGIZES WITH ANTI-PD-L1 TO PROMOTE DURABLE TEX REINVIGORATION. WE WILL ELUCIDATE THE MOLECULAR MECHANISMS OF SYNERGY BETWEEN MIR-29A AND ANTI-PD-L1 AND WE WILL DEFINE THE TET2-DEPENDENT AND TET2-INDEPENDENT ROLES OF MIR-29A IN SYNERGIZING WITH ANTI-PD-L1 IN MOUSE MODELS OF LCMV AND B16 MELANOMA.