Linoleic Acid Unleashes Potent Antitumor Immunity in CD8+ T Cells

In a groundbreaking study published in the prestigious journal Cell Metabolism, lead author Theresa Manzo supported by an international research team unveiled key findings that could revolutionize cancer immunotherapy. The study highlights the profound impact of linoleic acid on cytotoxic T cells, showcasing its potential to enhance the effectiveness of antitumor immune responses.

Recently it has been recognized that the metabolic state of CD8+ cytotoxic T cells is a key player in the immune response against tumors. Our interdisciplinary team, in this project under the leadership of Theresa Manzo,   discovered that specific lipids, when improperly regulated, can compromise CD8+ T cell mitochondrial integrity, leading to impaired antitumor responses. Notably, the newly published study demonstrates that linoleic acid emerges as a major positive regulator, bolstering CD8+ T cell activity and overcoming metabolic hurdles. By mitigating exhaustion, cytotoxic CD8+ T cells become capable of sustaining potent and prolonged antitumor responses, offering new possibilities for overcoming challenges in cancer treatment.

The study also shed light on the ability of linoleic acid to induce a memory-like phenotype in CD8+ T cells. This transformation equips the cells with superior effector functions, suggesting that linoleic acid treatment could play a crucial role in enhancing the longevity and effectiveness of immune responses against cancer. A deeper exploration into cellular dynamics revealed that linoleic acid treatment enhances the formation of ER-mitochondria contacts. This action promotes calcium (Ca2+) signaling, optimizes mitochondrial energetics, and boosts the effector functions of CD8+ T cells. 

As linoleic acid-instructed CD8+ T cells exhibited superior antitumor potency both in vitro and in vivo, this new study suggests linoleic acid treatment as an enhancer for more effective adoptive cellular immunotherapy against cancer. 

This work was supported by our German Research Council (DFG) research consortium  TRR221 GvH-GvL.

Reference:

Nava Lauson CB, Tiberti S, Corsetto P, Conte F, Punit T, Machwirth M, Ebert S, Loffreda A, Scheller L, Mokhtari Z, Sheta D, Peters T, Raman AT, Greco F, Rizzo A, Beilhack A, Signori G, Tumino N, Vacca P, McDonnell L, Raimondi A, Greenberg PD, Huppa JB, Cardaci S, Caruana I, Rodighiero S, Nezi L, Manzo T. (2023). Linoleic acid potentiates CD8+ T cell metabolic fitness and anti-tumor immunity. Cell Metabolism 35(4):633-650.e9.