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Supplementary Figure 1 from Antigen Priming Induces Functional Reprogramming in iNKT Cells via Metabolic and Epigenetic Regulation: An Insight into iNKT Cell-Based Antitumor Immunotherapy

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posted on 2023-12-01, 07:23 authored by Huimin Zhang, Sanwei Chen, Yuwei Zhang, Chenxi Tian, Jun Pan, Yu Wang, Shiyu Bai, Qielan Wu, Miya Su, Di Xie, Sicheng Fu, Shuhang Li, Jing Zhang, Yusheng Chen, Shasha Zhu, Yeben Qian, Li Bai

Antigen priming leads to dysfunction in distinct iNKT subsets.

Funding

the CAS Project for Young Scientists in Basic Research

Natural Science Foundation of Hefei

National Key Research and Development Program of China (NKPs)

National Natural Science Foundation of China (NSFC)

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ARTICLE ABSTRACT

Dysfunction of intratumoral invariant natural killer T (iNKT) cells hinders their antitumor efficacy, but the underlying mechanisms and the relationship with endogenous antigen priming remain to be explored. Here, we report that antigen priming leads to metabolic reprogramming and epigenetic remodeling, which causes functional reprogramming in iNKT cells, characterized by limited cytokine responses upon restimulation but constitutive high cytotoxicity. Mechanistically, impaired oxidative phosphorylation (OXPHOS) in antigen-primed iNKT cells inhibited T-cell receptor signaling, as well as elevation of glycolysis, upon restimulation via reducing mTORC1 activation, and thus led to impaired cytokine production. However, the metabolic reprogramming in antigen-primed iNKT cells was uncoupled with their enhanced cytotoxicity; instead, epigenetic remodeling explained their high expression of granzymes. Notably, intratumoral iNKT cells shared similar metabolic reprogramming and functional reprogramming with antigen-primed iNKT cells due to endogenous antigen priming in tumors, and thus recovery of OXPHOS in intratumoral iNKT cells by ZLN005 successfully enhanced their antitumor responses. Our study deciphers the influences of antigen priming-induced metabolic reprogramming and epigenetic remodeling on functionality of intratumoral iNKT cells, and proposes a way to enhance efficacy of iNKT cell-based antitumor immunotherapy by targeting cellular metabolism.

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