Data from Neutralization of Tumor Acidity Improves Antitumor Responses to Immunotherapy

• DOI: 10.1158/0008-5472.c.6507795
• Publication Date: 2023-04-01T01:49:11Z
• Authors: Shari Pilon-Thomas; Krithika N. Kodumudi; Asmaa E. El-Kenawi; Shonagh Russell; Amy M. Weber; Kimberly Luddy; Mehdi Damaghi; Jonathan W. Wojtk...; James J. Mulé; Arig Ibrahim-Hashim; Robert J. Gillies
• Keywords: Bicarbonate; Adoptive Cell Transfer; Cancer Immunotherapy; Immune checkpoint

<div>Abstract<p>Cancer immunotherapies, such as immune checkpoint blockade or adoptive T-cell transfer, can lead to durable responses in the clinic, but response rates remain low due undefined suppression mechanisms. Solid tumors are characterized by a highly acidic microenvironment that might blunt effectiveness of antitumor immunity. In this study, we directly investigated effects tumor acidity on efficacy immunotherapy. An pH environment blocked activation and limited glycolysis <i>in vitro</i>. IFNγ release did not occur at level steady-state mRNA, implying effect was posttranslational. Acidification affect cytoplasmic pH, suggesting signals transduced external were likely mediated specific acid-sensing receptors, four which expressed T cells. Notably, neutralizing with bicarbonate monotherapy impaired growth some cancer types mice where it associated increased infiltration. Furthermore, combining therapy anti-CTLA-4, anti-PD1, transfer improved multiple models, including cures subjects. Overall, our findings show how raising intratumoral through oral buffers improve immunotherapy, potential for immediate clinical translation. <i>Cancer Res; 76(6); 1381–90. ©2015 AACR</i>.</p></div>