title: Neutralization of Tumor Acidity Improves Antitumor Responses to Immunotherapy.
abstract: 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.
authors.affiliation: Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
authors.forename: Shari
authors.initials: S
authors.lastname: Pilon-Thomas
authors.affiliation: Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
authors.forename: Krithika N
authors.initials: KN
authors.lastname: Kodumudi
authors.affiliation: Department of Cancer Imaging and Metabolism, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
authors.forename: Asmaa E
authors.initials: AE
authors.lastname: El-Kenawi
authors.affiliation: Department of Cancer Imaging and Metabolism, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
authors.forename: Shonagh
authors.initials: S
authors.lastname: Russell
authors.affiliation: Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
authors.forename: Amy M
authors.initials: AM
authors.lastname: Weber
authors.affiliation: Department of Cancer Imaging and Metabolism, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Luddy
authors.affiliation: Department of Cancer Imaging and Metabolism, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Damaghi
authors.affiliation: Department of Cancer Imaging and Metabolism, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Wojtkowiak
authors.affiliation: Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
authors.forename: James J
authors.initials: JJ
authors.lastname: Mulé
authors.affiliation: Department of Cancer Imaging and Metabolism, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
authors.forename: Arig
authors.initials: A
authors.lastname: Ibrahim-Hashim
authors.affiliation: Department of Cancer Imaging and Metabolism, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. Robert.Gillies@moffitt.org.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Gillies
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology; D000970:Antineoplastic Agents / Q000276:immunology*; D001639:Bicarbonates / Q000494:pharmacology; D060908:CTLA-4 Antigen / Q000276:immunology; D045744:Cell Line, Tumor; D005260:Female; D006863:Hydrogen-Ion Concentration; D007167:Immunotherapy / Q000379:methods; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D059016:Tumor Microenvironment / Q000187:drug effects / Q000276:immunology*
chemical_list: D000906:Antibodies; D000970:Antineoplastic Agents; D001639:Bicarbonates; D060908:CTLA-4 Antigen; D061026:Programmed Cell Death 1 Receptor