Browsing by Author "Higashi, Richard M."

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    Asparagine restriction enhances CD8+ T cell metabolic fitness and antitumoral functionality through an NRF2-dependent stress response
    (Springer Nature, 2023) Gnanaprakasam, J. N. Rashida; Kushwaha, Bhavana; Liu, Lingling; Chen, Xuyong; Kang, Siwen; Wang, Tingting; Cassel, Teresa A.; Adams, Christopher M.; Higashi, Richard M.; Scott, David A.; Xin, Gang; Li, Zihai; Yang, Jun; Lane, Andrew N.; Fan, Teresa W. M.; Zhang, Ji; Wang, Ruoning; Pediatrics, School of Medicine
    Robust and effective T cell immune surveillance and cancer immunotherapy require proper allocation of metabolic resources to sustain energetically costly processes, including growth and cytokine production. Here, we show that asparagine (Asn) restriction on CD8+ T cells exerted opposing effects during activation (early phase) and differentiation (late phase) following T cell activation. Asn restriction suppressed activation and cell cycle entry in the early phase while rapidly engaging the nuclear factor erythroid 2-related factor 2 (NRF2)-dependent stress response, conferring robust proliferation and effector function on CD8+ T cells during differentiation. Mechanistically, NRF2 activation in CD8+ T cells conferred by Asn restriction rewired the metabolic program by reducing the overall glucose and glutamine consumption but increasing intracellular nucleotides to promote proliferation. Accordingly, Asn restriction or NRF2 activation potentiated the T cell-mediated antitumoral response in preclinical animal models, suggesting that Asn restriction is a promising and clinically relevant strategy to enhance cancer immunotherapy. Our study revealed Asn as a critical metabolic node in directing the stress signaling to shape T cell metabolic fitness and effector functions.
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    CD8+ T cell metabolic flexibility elicited by CD28-ARS2 axis-driven alternative splicing of PKM supports antitumor immunity
    (Springer Nature, 2024) Holling, G. Aaron; Chavel, Colin A.; Sharda, Anand P.; Lieberman, Mackenzie M.; James, Caitlin M.; Lightman, Shivana M.; Tong, Jason H.; Qiao, Guanxi; Emmons, Tiffany R.; Giridharan, Thejaswini; Hou, Shengqi; Intlekofer, Andrew M.; Higashi, Richard M.; Fan, Teresa W. M.; Lane, Andrew N.; Eng, Kevin H.; Segal, Brahm H.; Repasky, Elizabeth A.; Lee, Kelvin P.; Olejniczak, Scott H.; Medicine, School of Medicine
    Metabolic flexibility has emerged as a critical determinant of CD8+ T-cell antitumor activity, yet the mechanisms driving the metabolic flexibility of T cells have not been determined. In this study, we investigated the influence of the nuclear cap-binding complex (CBC) adaptor protein ARS2 on mature T cells. In doing so, we discovered a novel signaling axis that endows activated CD8+ T cells with flexibility of glucose catabolism. ARS2 upregulation driven by CD28 signaling reinforced splicing factor recruitment to pre-mRNAs and affected approximately one-third of T-cell activation-induced alternative splicing events. Among these effects, the CD28-ARS2 axis suppressed the expression of the M1 isoform of pyruvate kinase in favor of PKM2, a key determinant of CD8+ T-cell glucose utilization, interferon gamma production, and antitumor effector function. Importantly, PKM alternative splicing occurred independently of CD28-driven PI3K pathway activation, revealing a novel means by which costimulation reprograms glucose metabolism in CD8+ T cells.