Scientific publications

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

May 1, 2022 | Magazine: Oncoimmunology

Flor Navarro  1 , Noelia Casares  1 , Celia Martín-Otal  1 , Aritz Lasarte-Cía  1 , Marta Gorraiz  1 , Patricia Sarrión  1 , Diana Llopiz  1 , David Reparaz  1 , Nerea Varo  2 , Juan Roberto Rodriguez-Madoz  3 , Felipe Prosper  3   4 , Sandra Hervás-Stubbs  1 , Teresa Lozano  1 , Juan José Lasarte  1


Abstract

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.

CITATION  Oncoimmunology. 2022 May 1;11(1):2070337. doi: 10.1080/2162402X.2022.2070337. eCollection 2022. 

Our authors

Flor Navarro Negredo
Investigadora predoctoral del Programa de Inmunología e Inmunoterapia del Cima Universidad de Navarra
Celia Martín Otal
Aritz Lasarte Cía
Marta Gorraiz Ayala
Patricia Sarrión Pérez-Caballero
Diana Llópiz Khatchikian
David Repáraz Pernaut
Juan Roberto Rodríguez Madoz
Senior Researcher | Principal Investigator Multiple Myeloma Research Group
Sandra Hervás Stubbs
Researcher | Principal Investigator Immunology and Immunotherapy Research Program
Teresa Lozano Moreda