Linoleic acid potentiates CD8+ T cell metabolic fitness and antitumor immunity
Carina B. Nava Lauson, Silvia Tiberti, Paola Antonia Corsetto, Federica Conte, Punit Tyagi, Markus Machwirth, Stefan Ebert, Alessia Loffreda, Lukas Scheller, Dalia Sheta, Zeinab Mokhtari, Timo Peters, Ayush T. Raman, Francesco Greco, Angela Maria Rizzo, Andreas Beilhack, Giovanni Signore, Nicola Tumino, Paola Vacca, Liam A. McDonnell, Andrea Raimondi, Philip D. Greenberg, Johannes B. Huppa, Simone Cardaci, Ignazio Caruana, Simona Rodighiero, Luigi Nezi, Teresa Manzo
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 (Ca 2+ ) 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.