Journal
ONCOIMMUNOLOGY
Volume 11, Issue 1, Pages -Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/2162402X.2022.2070337
Keywords
Lymphocytes; intracellular pH; tumor microenvironment; AE2; HVCN1; adoptive cell therapy
Categories
Funding
- Ministerio de Educacion y Ciencia [SAF2016-78568-R, RTC-2017.6578-1]
- Ministerio de Ciencia e Innovacion [PID2019-108989RB-I00, PLEC2021-008094 MCIN/AEI/10.13039/501100011033]
- European Union NextGenerationEU/PRTR
- European Union [945393]
- Gobierno de Navarra [0011-1411-2019-000079, 0011-1411-2019-000072]
- Fundacion Ramon Areces
- Paula & Rodger Riney Foundation
- Juan de la Cierva grant [IJCI-2017-34204]
Ask authors/readers for more resources
The acidification of the tumor microenvironment inhibits the activity of antitumor T cells. Inhibiting the acid loader Ae2 enhances T cell function, while silencing Ae2 or overexpressing Hvcn1 improves the antitumor activity of T cells.
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available