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

Autor: Flor Navarro, Noelia Casares, Celia Martín-Otal, Aritz Lasarte-Cía, Marta Gorraiz, Patricia Sarrión, Diana Llopiz, David Reparaz, Nerea Varo, Juan Roberto Rodriguez-Madoz, Felipe Prosper, Sandra Hervás-Stubbs, Teresa Lozano, Juan José Lasarte
Jazyk: angličtina
Rok vydání: 2022
Předmět:
Zdroj: OncoImmunology, Vol 11, Iss 1 (2022)
Druh dokumentu: article
ISSN: 2162402X
2162-402X
DOI: 10.1080/2162402X.2022.2070337
Popis: 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.
Databáze: Directory of Open Access Journals
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