Ep. 60: “Immunometabolism and Cancer Immunotherapy” Featuring Dr. Greg Delgoffe
Aug 15, 2023
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Dr. Greg Delgoffe, an Associate Professor at the University of Pittsburgh studying metabolism and immunity in cancer, discusses the metabolism of immune cells in cancer and the effects of nutrients in the tumor microenvironment. Topics include the role of immunometabolism in autoimmunity, CD8 T cells killing MHC one negative tumor cells, and the Warburg effect in tumor metabolism.
CD8 T cells can recognize and kill MHC class I deficient tumor cells, providing an alternative immune surveillance against cancer.
Targeting the STING pathway could be a potential therapeutic approach for age-related neurodegenerative diseases by reducing inflammation in the brain.
Understanding the metabolic adaptations of Treg cells in the tumor microenvironment could lead to the development of targeted therapies enhancing anti-tumor immune responses.
Deep dives
CD8 T cells can kill MHC-negative tumor cells
CD8 T cells have the ability to kill tumor cells lacking MHC class I through the NKG2D/NKG2DL axis. This mechanism allows CD8 T cells to recognize and kill tumor cells that have lost MHC expression, providing an alternative way for immune surveillance against cancer.
Sting pathway drives aging-related inflammation and neurodegeneration
Activation of the sting pathway in aging leads to increased inflammation in the brain and neurodegeneration. By blocking the sting pathway, researchers were able to reduce the levels of inflammatory cytokines and prevent neurodegenerative changes in the brain, suggesting that targeting this pathway could be a potential therapeutic approach for age-related neurodegenerative diseases.
Metabolism of T regulatory cells and its implications in cancer
T regulatory (Treg) cells have a distinct metabolic profile that allows them to thrive in the tumor microenvironment. They preferentially utilize lactate, a metabolite produced by tumors, which promotes their survival and suppressive function. Understanding the metabolic adaptations of Treg cells in cancer could lead to the development of targeted therapies that disrupt their metabolic pathways and enhance anti-tumor immune responses.
Recognition of Tumors in Immunotherapy
The podcast discusses a study on the recognition and rejection of tumors in immunotherapy. It was found that checkpoint inhibition can lead to robust recognition and rejection of tumors, even in the absence of NK cells. The study reveals that CD8 cells play a crucial role in mediating this response, and they don't necessarily need to be tumor-specific. The activation of CD8 cells by macrophages presenting antigens is key in redirecting the cytotoxic activity of CD8 cells onto tumors. This recognition is mediated by ligands of the NKG2D molecule, which are overexpressed in the tumors. Importantly, this recognition is specific to the tumor and most healthy tissues are spared.
Understanding Immunometabolism in Cancer Research
The podcast conversation delves into the field of immunometabolism and its impact on cancer research. It emphasizes the significance of considering metabolic environments in the regulation of T cells. Mitochondria play a crucial role in cellular metabolism, not only in generating energy but also in producing biosynthetic intermediates. The morphology of mitochondria affects the survival and function of T cells, with more complex and fused mitochondria being more fuel-efficient and productive in terms of biosynthesis. The discussion highlights the potential of manipulating mitochondria for therapeutic purposes, such as through mitochondrial transfusions and promoting mitochondrial biogenesis. Understanding the interplay between metabolism and immune cells opens up new avenues for cancer treatment and anti-aging research.
Dr. Greg Delgoffe is an Associate Professor at the University of Pittsburgh. His lab studies the intersection of metabolism and immunity in cancer. He talks about the metabolism of immune cells in cancer and the effects of nutrients in the tumor microenvironment.
STING Can Transport Protons – Scientists analyzed STING’s structure, hypothesizing that its transmembrane domain forms a pore capable of proton transport.
cGAS–STING in Neurodegeneration – The cGAS–STING signaling pathway is a critical driver of chronic inflammation and functional decline during aging.
