A5085469360- Immune Cell Function and Interaction
- T-cell and B-cell Immunology
- Immunotherapy and Immune Responses
- Cancer Immunotherapy and Biomarkers
- CAR-T cell therapy research
- Cancer-related gene regulation
- Immune cells in cancer
- Single-cell and spatial transcriptomics
- Genomics, phytochemicals, and oxidative stress
- Virus-based gene therapy research
- Autophagy in Disease and Therapy
- Gut microbiota and health
- Wnt/β-catenin signaling in development and cancer
- Peptidase Inhibition and Analysis
- Kruppel-like factors research
- Diabetes and associated disorders
- CRISPR and Genetic Engineering
Yale University
2024-2025
University of Pennsylvania
2016-2021
Translational Therapeutics (United States)
2020-2021
Naïve CD8 T cells have the potential to differentiate into a spectrum of functional states during an immune response. How these developmental decisions are made and what mechanisms exist suppress differentiation toward alternative fates remains unclear. We employed in vivo CRISPR-Cas9–based perturbation sequencing assess role ~40 transcription factors (TFs) epigenetic modulators cell fate decisions. Unexpectedly, we found that knockout TF Klf2 resulted aberrant exhausted-like acute...
The transcription factors T-bet and Eomesodermin (Eomes) regulate CD8 T cell exhaustion through undefined mechanisms. Here, we show that the subcellular localization of Eomes dictate their regulatory activity in exhausted cells (TEXs). TEXs had a higher ratio nuclear Eomes:T-bet than memory (TMEMs) during chronic lymphocytic choriomeningitis virus (LCMV) infection preclinical cancer models human tumors. Biochemically, compete for same DNA sequences, including Pdcd1 T-box. High strongly...
An early memory CD8 + T cell precursor with distinct genome maintenance capacity depends on inhibitory receptor signaling.
New strategies are needed to enhance the efficacy of anti–programmed cell death protein antibody (anti–PD-1 Ab) in cancer. Here, we report that inhibiting palmitoyl-protein thioesterase 1 (PPT1), a target chloroquine derivatives like hydroxychloroquine (HCQ), enhances antitumor anti–PD-1 Ab melanoma. The combination resulted tumor growth impairment and improved survival mouse models. Genetic suppression core autophagy genes, but not Ppt1, cancer cells reduced priming cytotoxic capacity...
Abstract Overcoming acquired adaptive immune resistance to anti-PD-1 therapy is imperative for enhancing the efficacy of checkpoint blockade (ICB) in solid tumors. Regulatory T cells (Tregs) play a prominent role suppressive tumor microenvironment (TME) and are major contributors resistance. Tregs limit CD8+ cell reinvigoration promising target combination therapy. While clinical anti-CTLA4 may be partially explained by restriction Tregs, its co-administration with anti-PD1 causes...
Abstract Dynamic reprogramming of metabolism is essential for T cell effector function and formation memory. However, regulation cellular in exhausted cells chronic infections cancer poorly understood. Here we found that as early the first week LCMV infection, before severe dysfunction becomes established, virus-specific CD8 are already unable to match bioenergetic demands generated during acutely resolving infection. Suppression bioenergetics involves restriction glucose uptake utilization,...
Abstract Following acute viral infection, effector CD8 T-cells (TE) differentiate into long-lived memory cells (TMEM) required for secondary clearance. Due to persisting antigen in chronic rather than differentiating TMEM, TE progressively lose their functional abilities and become exhausted (TEX), expressing high levels of the inhibitory receptor PD1. Differentiation TE, TEX is driven by transcription factors including T-bet Eomes. In represses PD1 while Eomes drives formation. PD1+ TEX,...