Neutralization of Tumor Acidity Improves Antitumor Responses to Immunotherapy

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 to undefined suppression mechanisms. Solid tumors are characterized by a highly acidic microenvironment that might blunt the effectiv...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2016-03, Vol.76 (6), p.1381-1390
Main Authors: Pilon-Thomas, Shari, Kodumudi, Krithika N, El-Kenawi, Asmaa E, Russell, Shonagh, Weber, Amy M, Luddy, Kimberly, Damaghi, Mehdi, Wojtkowiak, Jonathan W, Mulé, James J, Ibrahim-Hashim, Arig, Gillies, Robert J
Format: Article
Language:English
Subjects:
Animals
Antibodies - immunology
Antineoplastic Agents - immunology
Bicarbonates - pharmacology
Cell Line, Tumor
CTLA-4 Antigen - immunology
Female
Hydrogen-Ion Concentration
Immunotherapy - methods
Lymphocyte Activation - drug effects
Lymphocyte Activation - immunology
Mice
Mice, Inbred C57BL
Programmed Cell Death 1 Receptor - immunology
T-Lymphocytes - drug effects
T-Lymphocytes - immunology
Tumor Microenvironment - drug effects
Tumor Microenvironment - immunology
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Summary: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 to undefined suppression mechanisms. Solid tumors are characterized by a highly acidic microenvironment that might blunt the effectiveness of antitumor immunity. In this study, we directly investigated the effects of tumor acidity on the efficacy of immunotherapy. An acidic pH environment blocked T-cell activation and limited glycolysis in vitro. IFNγ release blocked by acidic pH did not occur at the level of steady-state mRNA, implying that the effect of acidity was posttranslational. Acidification did not affect cytoplasmic pH, suggesting that signals transduced by external acidity were likely mediated by specific acid-sensing receptors, four of which are expressed by T cells. Notably, neutralizing tumor acidity with bicarbonate monotherapy impaired the growth of some cancer types in mice where it was associated with increased T-cell infiltration. Furthermore, combining bicarbonate therapy with anti-CTLA-4, anti-PD1, or adoptive T-cell transfer improved antitumor responses in multiple models, including cures in some subjects. Overall, our findings show how raising intratumoral pH through oral buffers therapy can improve responses to immunotherapy, with the potential for immediate clinical translation.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.can-15-1743