Metabolic regulation of anti-tumor immunity

Ergin, Ilgin (May 2023) Metabolic regulation of anti-tumor immunity. PhD thesis, Cold Spring Harbor Laboratory.

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Abstract

Accumulating evidence suggests that nutrients are not only crucial for generating energy and biosynthetic precursors (Warburg et al. 1927; Vander Heiden et al. 2009; Zhu and Thompson 2019), but can also directly regulate cell fate and function (Ryall et al. 2015a; Ly et al. 2020). Nutrients and their metabolites can regulate the fate and function of diverse cell types by activating nutrient-sensing signaling pathways, regulating transcription factor activity, and remodeling the epigenetic landscape. (Evans and Mangelsdorf 2014; Berger and Sassone-Corsi 2016; Saxton and Sabatini 2017). However, precise mechanisms of how metabolic reprogramming influences cell fate and function remain elusive. Metabolic reprogramming is particularly important for rapidly proliferating cells such as malignant cells. Cancer cells increase both glycolytic and oxidative metabolism in order to optimize the production of energy, biosynthetic precursors, and oncometabolites (DeBerardinis and Chandel 2016; DeBerardinis and Chandel 2020). Tumor infiltrating immune cells rely on similar metabolic pathways to cancer cells (Pearce and Pearce 2013; Leone and Powell 2020). This convergence of metabolic demands is argued to give rise to a “metabolic tug-of-war” in the tumor microenvironment (TME) and dampen the function of tumor infiltrating immune cells (Chang et al. 2015; Ho et al. 2015; Buck et al. 2017; Ringel et al. 2020). Previous work from our lab has shown that a long-term high-fat diet promotes intestinal stem cell activity and tumorigenicity through stem cell-intrinsic activation of lipid-sensing transcription factor peroxisome proliferator activated receptor δ (PPARδ) (Beyaz et al. 2016; Beyaz et al. 2021b). Recent findings suggest that fatty acids in the TME are preferentially taken up by cancer cells and immune cell fatty acid deprivation dampens anti-tumor immunity (Ringel et al. 2020; Reinfeld et al. 2021). However, there are contradictory results on the effects of PPARδ mediated fatty acid metabolism on anti-tumor immunity (Zhang et al. 2017; Chowdhury et al. 2018; Raud et al. 2018; Saibil et al. 2019; Wang et al. 2020a). Furthermore, how PPARδ and PPARδ-induced metabolic reprogramming affects immune cell fate and function remain to be elucidated (Christofides et al. 2021). Therefore, here we study the significance of PPARδ signaling in immune cells for anti-tumor immune response. Using new immune lineage specific PPARδ gain-of-function and loss-of-function mouse models, we show that PPARδ activation in immune cells promotes anti-tumor immunity regardless of cancer type or immunogenicity, without causing any adverse effects. CD8 T cells are necessary and sufficient for PPARδ mediated anti-tumor immunity, and PPARδ activation in myeloid cells is sufficient to promote anti-tumor immunity in a CD8 T cell dependent manner. Mechanistically, PPARδ target carnitine palmitoyltransferase 1a (Cpt1a), rate limiting enzyme of mitochondrial fatty acid β-oxidation (FAO), in part mediates the effects of PPARδ on anti-tumor immunity. Furthermore, our results demonstrate that PPARδ activation in human chimeric antigen receptor T (CAR-T) cells is sufficient to boost CAR-T cell cytotoxicity. Our findings pave the way for the development of novel immunotherapies that promote immune cell metabolic fitness through PPARδ-Cpt1a axis.

Item Type:	Thesis (PhD)
Subjects:	diseases & disorders > cancer diseases & disorders organs, tissues, organelles, cell types and functions > cell types and functions > cell functions organs, tissues, organelles, cell types and functions > cell types and functions organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > immunity organs, tissues, organelles, cell types and functions
CSHL Authors:	Ergin, Ilgin
Communities:	CSHL labs > Beyaz lab School of Biological Sciences > Theses
Depositing User:	Kathleen McGuire
Date:	31 May 2023
Date Deposited:	06 May 2024 19:43
Last Modified:	06 May 2024 19:43
URI:	https://repository.cshl.edu/id/eprint/41531

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