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

Area of Science:

• Immunology
• Cancer Biology
• Molecular Biology

Background:

• Tumor microenvironment (TME) acidification, caused by high metabolic activity and poor perfusion, can suppress anti-tumor T cell responses.
• Chloride/bicarbonate anion exchanger 2 (Ae2) acts as an acid loader, potentially contributing to T cell dysfunction in acidic TME.
• Hvcn1 is an outward proton current mediator that can prevent cellular acidification.

Purpose of the Study:

• To investigate the impact of modulating Ae2 and Hvcn1 on T cell function and anti-tumor activity within the acidic TME.
• To evaluate the therapeutic potential of targeting these ion channels for cancer immunotherapy.

Main Methods:

• Pharmacological inhibition of Ae2 using DIDS (4,4'-diisothiocyanatostilbene-2,2'-disulfonicacid) in T cells.
• Genetic silencing of Ae2 and overexpression of Hvcn1 in OVA-specific T cells and CAR T cells.
• In vitro assessment of T cell function (TCR activation) under varying pH conditions.
• In vivo studies using B16OVA and PM299L-GPC3 tumor models in mice, evaluating tumor growth and T cell-mediated anti-tumor activity.

Main Results:

• DIDS treatment enhanced CD4+ and CD8+ T cell function in vitro, particularly at low pH, and delayed tumor growth in vivo.
• Genetic Ae2 silencing and Hvcn1 overexpression in T cells improved their function and anti-tumor efficacy both in vitro and in vivo.
• Hvcn1 overexpression also enhanced the anti-tumor activity of GPC3-specific CAR T cells.

Conclusions:

• Preventing intracellular acidification in tumor-specific lymphocytes by targeting Ae2 or Hvcn1 can enhance their anti-tumor responses.
• Modulating these ion channels makes T cells more resistant to the acidic TME, offering a promising strategy for improving cancer immunotherapy.