Exhaustion
Exhaustion
Cell Stress Signaling Responses in Tumor Immunity
Our laboratory studies the mechanisms through which immune cells in tumors experience tumor microenvironment (TME) stress. We have found that TME stressors such as hypoxia enforce ER stress proteins in T cells and macrophages in tumors promoting cellular dysfunction, such as T cell exhaustion. We utilize Opal multiplex immunofluorescent imaging, spectral flow cytometry, metabolomics, Seahorse Bioanalysis, tumor mouse models and patient samples to study the chronic stress response in tumor immunity.
We continue to study the role of unfolded protein response (UPR) and integrated stress response (ISR) pathways to program immune cell fate and function in tumors. Our latest work in Immunity details the role of chronic ISR element ATF4 in this process.
Metabolic Reprogramming of Immunity
Metabolism of tumor infiltrating T cells (TILs) and tumor associated macrophages defines their antitumor capacity. We study how immune cell stress in the tumor microenvironment programs aberrant metabolism in CD8+ TILs and tumor associated macrophages to limit response to checkpoint therapies.
We continue to study the role of lipogenesis to aberrantly program immune cell fate and function in tumors. Our latest work in Cell Metabolism details the role of the tumor microenvironment to drive the metabolic enzyme ACC to promote lipid accumulation in T cells in tumors.
Organelle Homeostasis in Immunity
Organelle structure underlies healthy cellular function. We study the morphology of the endoplasmic reticulum and mitochondria in T cells and macrophages in the stress of the tumor microenvironment. We have used multiple innovative techniques to identify that the tumor microenvironment damages and dysregulates organelle structure in CD8+ T cells in tumors. We are studying strategies to modulate organelle structure in endogenous immunity and CAR-T cells to promote long-term antitumor immunity.
We have identified that endoplasmic reticulum structure is altered in T cells in tumors and that this is driven by endoplasmic reticulum structural protein CKAP4. This work is under review, Immunity.
Funding
Common Laboratory Techniques
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Spectral Flow Cytometry
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Multiplex imaging
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Confocal imaging
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RNA-sequencing
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Single-cell RNA-sequencing
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Spatial transcriptomics
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Seahorse bioanalysis
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Metabolomics
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Proteomics