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Overcoming T cell dysfunction in acidic pH to enhance adoptive T cell transfer immunotherapy

2022; Landes Bioscience; Volume: 11; Issue: 1 Linguagem: Inglês

10.1080/2162402x.2022.2070337

2162-402X

Flor Navarro, Noëlia Casares, Celia Martín-Otal, Aritz Lasarte-Cía, Marta Gorraiz, Patricia Sarrión, Diana Llópiz, David Repáraz, Nerea Varo, Juan R. Rodríguez-Madoz, Felipe Prósper, Sandra Hervás‐Stubbs, Teresa Lozano, Juan José Lasarte,

Adenosine and Purinergic Signaling

The high metabolic activity and insufficient perfusion of tumors leads to the acidification of the tumor microenvironment (TME) that may inhibit the antitumor T cell activity. We found that pharmacological inhibition of the acid loader chloride/bicarbonate anion exchanger 2 (Ae2), with 4,4'-diisothiocyanatostilbene-2,2'-disulfonicacid (DIDS) enhancedCD4+ andCD8+ T cell function upon TCR activation in vitro, especially under low pH conditions. In vivo, DIDS administration delayed B16OVA tumor growth in immunocompetent mice as monotherapy or when combined with adoptive T cell transfer of OVA-specificT cells. Notably, genetic Ae2 silencing in OVA-specificT cells improvedCD4+/CD8+ T cell function in vitro as well as their antitumor activity in vivo. Similarly, genetic modification of OVA-specificT cells to overexpress Hvcn1, a selectiveH+ outward current mediator that prevents cell acidification, significantly improved T cell function in vitro, even at low pH conditions. The adoptive transfer of OVA-specificT cells overexpressing Hvcn1 exerted a better antitumor activity in B16OVA tumor-bearingmice. Hvcn1 overexpression also improved the antitumor activity of CAR T cells specific for Glypican 3 (GPC3) in mice bearing PM299L-GPC3tumors. Our results suggest that preventing intracellular acidification by regulating the expression of acidifier ion channels such as Ae2 or alkalinizer channels like Hvcn1 in tumor-specificlymphocytes enhances their antitumor response by making them more resistant to the acidic TME.