The metabolic state represents a major hurdle for an effective adoptive T cell therapy (ACT). Indeed, specific lipids can harm CD8+ T cell (CTL) mitochondrial integrity, leading to defective antitumor responses. However, the extent to which lipids can affect the CTL functions and fate remains unexplored. Here, we show that linoleic acid (LA) is a major positive regulator of CTL activity by improving metabolic fitness, preventing exhaustion, and stimulating a memory-like phenotype with superior effector functions. We report that LA treatment enhances the formation of ER-mitochondria contacts (MERC), which in turn promotes calcium (Ca2+) signaling, mitochondrial energetics, and CTL effector functions. As a direct consequence, the antitumor potency of LA-instructed CD8 T cells is superior in vitro and in vivo. We thus propose LA treatment as an ACT potentiator in tumor therapy.

Linoleic acid potentiates CD8+ T cell metabolic fitness and antitumor immunity / C.B. Nava Lauson, S. Tiberti, P.A. Corsetto, F. Conte, P. Tyagi, M. Machwirth, S. Ebert, A. Loffreda, L. Scheller, D. Sheta, Z. Mokhtari, T. Peters, A.T. Raman, F. Greco, A.M. Rizzo, A. Beilhack, G. Signore, N. Tumino, P. Vacca, L.A. Mcdonnell, A. Raimondi, P.D. Greenberg, J.B. Huppa, S. Cardaci, I. Caruana, S. Rodighiero, L. Nezi, T. Manzo. - In: CELL METABOLISM. - ISSN 1550-4131. - 35:4(2023 Apr 04), pp. 633-650e9. [10.1016/j.cmet.2023.02.013]

Linoleic acid potentiates CD8+ T cell metabolic fitness and antitumor immunity

C.B. Nava Lauson
Primo
;
S. Tiberti
Secondo
;
P.A. Corsetto;A.M. Rizzo;
2023

Abstract

The metabolic state represents a major hurdle for an effective adoptive T cell therapy (ACT). Indeed, specific lipids can harm CD8+ T cell (CTL) mitochondrial integrity, leading to defective antitumor responses. However, the extent to which lipids can affect the CTL functions and fate remains unexplored. Here, we show that linoleic acid (LA) is a major positive regulator of CTL activity by improving metabolic fitness, preventing exhaustion, and stimulating a memory-like phenotype with superior effector functions. We report that LA treatment enhances the formation of ER-mitochondria contacts (MERC), which in turn promotes calcium (Ca2+) signaling, mitochondrial energetics, and CTL effector functions. As a direct consequence, the antitumor potency of LA-instructed CD8 T cells is superior in vitro and in vivo. We thus propose LA treatment as an ACT potentiator in tumor therapy.
CD8 T cells; adoptive T cell therapy; linoleic acid; lipid metabolism; metabolic fitness
Settore BIO/10 - Biochimica
4-apr-2023
9-mar-2023
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/963060
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