CoChat
Sign Up
Cited by 593Cancer Immunotherapy and BiomarkersCancer, Hypoxia, and MetabolismImmunotherapy and Immune Responses

Neutralization of Tumor Acidity Improves Antitumor Responses to Immunotherapy

Open access
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.·2016·Cancer Research
DOI 10.1158/0008-5472.can-15-1743PMC PMC4829106

Published version of a preprint

Open this paper in CoChat — free account

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.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1158/0008-5472.can-15-1743

Cites

5 of 5 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Cancer cells compete with immune cells for glucose uptake (by SLC2A1/GLUT1), produce lactic acid (by LDHA), and generate an acidic extracellular milieu (through the activity of CA9), all of which are immunosuppressive.

    “Cancer cells compete with immune cells for glucose uptake (by SLC2A1/GLUT1), produce lactic acid (by LDHA), and generate an acidic extracellular milieu (through the activity of CA9), all of which are immunosuppressive (77–86).”

    From HIF inhibitor 32-134D eradicates murine hepatocellular carcinoma in combination with anti-PD1 therapy (2022) · cites this paper as [86]

    The Introduction (page not provided) links extracellular tumor acidity to carbonic anhydrase IX (CAIX), also called CA9. The Discussion (page not provided) reports that acidic tumor pH suppresses T-cell responses. The paper does not establish glucose competition through SLC2A1/GLUT1 or lactic-acid production through LDHA, so it supports only the acidity-related part of the claim. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 44

  1. [1]Schneider H Downey J Smith A Zinselmeyer BH Rush C Brewer JM Reversal of the TCR stop signal by CTLA-4 Science 2006 313 5795 1972 5 16931720
  2. [2]Vesely MD Kershaw MH Schreiber RD Smyth MJ Natural innate and adaptive immunity to cancer Annual review of immunology 2011 29 235 71 21219185
  3. [3]Hodi FS O’Day SJ McDermott DF Weber RW Sosman JA Haanen JB Improved survival with ipilimumab in patients with metastatic melanoma The New England journal of medicine 2010 363 8 711 23 20525992 PMC3549297
  4. [4]Topalian SL Sznol M McDermott DF Kluger HM Carvajal RD Sharfman WH Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab Journal of clinical oncology: official journal of the American Society of Clinical Oncology 2014 32 10 1020 30 24590637 PMC4811023
  5. [5]Taube JM Klein A Brahmer JR Xu H Pan X Kim JH Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy Clinical cancer research: an official journal of the American Association for Cancer Research 2014 20 19 5064 74 24714771 PMC4185001
  6. [6]Topalian SL Hodi FS Brahmer JR Gettinger SN Smith DC McDermott DF Safety, activity, and immune correlates of anti-PD-1 antibody in cancer The New England journal of medicine 2012 366 26 2443 54 22658127 PMC3544539
  7. [7]Wolchok JD Neyns B Linette G Negrier S Lutzky J Thomas L Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study The Lancet Oncology 2010 11 2 155 64 20004617
  8. [8]Fourcade J Sun Z Benallaoua M Guillaume P Luescher IF Sander C Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients The Journal of experimental medicine 2010 207 10 2175 86 20819923 PMC2947081
  9. [9]Fourcade J Sun Z Pagliano O Guillaume P Luescher IF Sander C CD8(+) T cells specific for tumor antigens can be rendered dysfunctional by the tumor microenvironment through upregulation of the inhibitory receptors BTLA and PD-1 Cancer research 2012 72 4 887 96 22205715 PMC3288235
  10. [10]Yang ZZ Grote DM Ziesmer SC Niki T Hirashima M Novak AJ IL-12 upregulates TIM-3 expression and induces T cell exhaustion in patients with follicular B cell non-Hodgkin lymphoma The Journal of clinical investigation 2012 122 4 1271 82 22426209 PMC3314462
  11. [12]Diaz-Montero CM Salem ML Nishimura MI Garrett-Mayer E Cole DJ Montero AJ Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin-cyclophosphamide chemotherapy Cancer immunology, immunotherapy: CII 2009 58 1 49 59 18446337 PMC3401888
  12. [13]Pilon-Thomas S Nelson N Vohra N Jerald M Pendleton L Szekeres K Murine pancreatic adenocarcinoma dampens SHIP-1 expression and alters MDSC homeostasis and function PloS one 2011 6 11 e27729 22132131 PMC3222660
  13. [14]Matsushita N Pilon-Thomas SA Martin LM Riker AI Comparative methodologies of regulatory T cell depletion in a murine melanoma model Journal of immunological methods 2008 333 1–2 167 79 18295790 PMC2577585
  14. [15]Peranzoni E Zilio S Marigo I Dolcetti L Zanovello P Mandruzzato S Myeloid-derived suppressor cell heterogeneity and subset definition Current opinion in immunology 2010 22 2 238 44 20171075
  15. [16]Nagaraj S Gabrilovich DI Myeloid-derived suppressor cells in human cancer Cancer journal 2010 16 4 348 53 20693846
  16. [18]Fallarino F Grohmann U Puccetti P Indoleamine 2,3-dioxygenase: from catalyst to signaling function European journal of immunology 2012 42 8 1932 7 22865044
  17. [19]Lardner A The effects of extracellular pH on immune function Journal of leukocyte biology 2001 69 4 522 30 11310837
  18. [20]Ibrahim Hashim A Zhang X Wojtkowiak JW Martinez GV Gillies RJ Imaging pH and metastasis NMR in biomedicine 2011 24 6 582 91 21387439 PMC3740268
  19. [21]Gatenby RA Gillies RJ Why do cancers have high aerobic glycolysis? Nature reviews Cancer 2004 4 11 891 9 15516961
  20. [22]Swietach P Hulikova A Vaughan-Jones RD Harris AL New insights into the physiological role of carbonic anhydrase IX in tumour pH regulation Oncogene 2010 29 50 6509 21 20890298
  21. [23]Choi J Jung WH Koo JS Metabolism-related proteins are differentially expressed according to the molecular subtype of invasive breast cancer defined by surrogate immunohistochemistry Pathobiology: journal of immunopathology, molecular and cellular biology 2013 80 1 41 52 22832328
  22. [24]Ilie M Mazure NM Hofman V Ammadi RE Ortholan C Bonnetaud C High levels of carbonic anhydrase IX in tumour tissue and plasma are biomarkers of poor prognostic in patients with non-small cell lung cancer British journal of cancer 2010 102 11 1627 35 20461082 PMC2883156
  23. [25]Choschzick M Oosterwijk E Muller V Woelber L Simon R Moch H Overexpression of carbonic anhydrase IX (CAIX) is an independent unfavorable prognostic marker in endometrioid ovarian cancer Virchows Archiv: an international journal of pathology 2011 459 2 193 200 21691815
  24. [26]Estrella V Chen T Lloyd M Wojtkowiak J Cornnell HH Ibrahim-Hashim A Acidity generated by the tumor microenvironment drives local invasion Cancer research 2013 PMC3594450 23288510
  25. [27]Ibrahim Hashim A Cornnell HH Coelho Ribeiro Mde L Abrahams D Cunningham J Lloyd M Reduction of metastasis using a non-volatile buffer Clinical & experimental metastasis 2011 28 8 841 9 21861189 PMC3213349
  26. [28]Robey IF Baggett BK Kirkpatrick ND Roe DJ Dosescu J Sloane BF Bicarbonate increases tumor pH and inhibits spontaneous metastases Cancer research 2009 69 6 2260 8 19276390 PMC2834485
  27. [29]Noritomi DT Soriano FG Kellum JA Cappi SB Biselli PJ Liborio AB Metabolic acidosis in patients with severe sepsis and septic shock: a longitudinal quantitative study Critical care medicine 2009 37 10 2733 9 19885998
  28. [31]Vishvakarma NK Singh SM Immunopotentiating effect of proton pump inhibitor pantoprazole in a lymphoma-bearing murine host: Implication in antitumor activation of tumor-associated macrophages Immunology letters 2010 134 1 83 92 20837061
  29. [32]Vishvakarma NK Singh SM Augmentation of myelopoiesis in a murine host bearing a T cell lymphoma following in vivo administration of proton pump inhibitor pantoprazole Biochimie 2011 93 10 1786 96 21722701
  30. [33]Bental M Deutsch C An NMR view of Primary T-Lymphocyte Activation Gillies RJ NMR in Physiology and Biomedicine 1 New York Academic Press 1994
  31. [34]Damaghi M Wojtkowiak JW Gillies RJ pH sensing and regulation in cancer Frontiers in physiology 2013 4 370 24381558 PMC3865727
  32. [35]Ishii S Kihara Y Shimizu T Identification of T cell death-associated gene 8 (TDAG8) as a novel acid sensing G-protein-coupled receptor The Journal of biological chemistry 2005 280 10 9083 7 15618224
  33. [36]Li Z Dong L Dean E Yang LV Acidosis decreases c-Myc oncogene expression in human lymphoma cells: a role for the proton-sensing G protein-coupled receptor TDAG8 International journal of molecular sciences 2013 14 10 20236 55 24152439 PMC3821613
  34. [37]Cougoule C Van Goethem E Le Cabec V Lafouresse F Dupre L Mehraj V Blood leukocytes and macrophages of various phenotypes have distinct abilities to form podosomes and to migrate in 3D environments European journal of cell biology 2012 91 11–12 938 49 22999511
  35. [38]Hulikova A Harris AL Vaughan-Jones RD Swietach P Regulation of intracellular pH in cancer cell lines under normoxia and hypoxia Journal of cellular physiology 2013 228 4 743 52 22949268
  36. [39]Chang CH Curtis JD Maggi LB Jr Faubert B Villarino AV O’Sullivan D Posttranscriptional control of T cell effector function by aerobic glycolysis Cell 2013 153 6 1239 51 23746840 PMC3804311
  37. [40]Ibrahim Hashim A Wojtkowiak JW Ribeiro M Estrella V Bailey KM Cornnell HH Free Base Lysine Increases Survival and Reduces Metastasis in Prostate Cancer Model J Cancer Sci Therap 2011 2011 S1 S4 PMC3768133 24032073
  38. [41]Ibrahim-Hashim A Cornnell HH Abrahams D Lloyd M Bui M Gillies RJ Systemic buffers inhibit carcinogenesis in TRAMP mice The Journal of urology 2012 188 2 624 31 22704445 PMC3694604
  39. [44]McCoy KD Le Gros G The role of CTLA-4 in the regulation of T cell immune responses Immunology and cell biology 1999 77 1 1 10 10101680
  40. [45]Robbins PF Dudley ME Wunderlich J El-Gamil M Li YF Zhou J Cutting edge: persistence of transferred lymphocyte clonotypes correlates with cancer regression in patients receiving cell transfer therapy Journal of immunology 2004 173 12 7125 30 PMC2175171 15585832
  41. [46]Damaghi M Tafreshi NK Lloyd M Sprung R Estrella V Wojtkowiak JW Chronic Acidosis in the Tumor Microenvironment Selects for Overexpression of LAMP2 in the Plasma Membrane NAture Comminications 2016 (in press) PMC4682176 26658462
  42. [47]Silva AS Yunes JA Gillies RJ Gatenby RA The potential role of systemic buffers in reducing intratumoral extracellular pH and acid-mediated invasion Cancer research 2009 69 6 2677 84 19276380 PMC3718046
  43. [49]Ashby BS pH studies in human malignant tumours Lancet 1966 2 7458 312 5 4161494
  44. [50]Dong L Li Z Leffler NR Asch AS Chi JT Yang LV Acidosis activation of the proton-sensing GPR4 receptor stimulates vascular endothelial cell inflammatory responses revealed by transcriptome analysis PloS one 2013 8 4 e61991 23613998 PMC3628782

Cited by

Sorted by citations

Authors
Pilon-Thomas, S., Kodumudi, K. N., El-Kenawi, A. E., Russell, S., Weber, A. M., Luddy, K., Damaghi, M., Wojtkowiak, J. W., Mulé, J. J., Ibrahim-Hashim, A., & Gillies, R. J.
Affiliations
  • 1Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
  • Moffitt Cancer Center (US)
  • Mansoura University (EG)
  • 2Department of Cancer Imaging and Metabolism, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
Corresponding author
Gillies, Robert J.
ORCID
Venue
Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2016-03-14
Volume
76
Issue
6
Pages
1381-1390
ISSN
  • 0008-5472 (ISSN-L)
  • 1538-7445
DOI
10.1158/0008-5472.can-15-1743
PMC
PMC4829106
OpenAlex
W2291579888
Cited by
593
References
5
Citations by year
2026: 41 · 2025: 40 · 2024: 59 · 2023: 65 · 2022: 93 · 2021: 70 · 2020: 81 · 2019: 62 · 2018: 31 · 2017: 34 · 2016: 17
FWCI
25.89
Type
journal article
Language
en
Open access
Locations
  • Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • USPHS (R01CA077575, P50CA168536)
  • Moffitt Cancer Center (P30CA076292)
Topics
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords
tumor acidosis, bicarbonate therapy, cancer immunotherapy, immune checkpoint blockade, anti-CTLA-4, anti-PD-1, adoptive T cell therapy, T cell activation, glycolysis, IFN-gamma secretion, T cell infiltration
MeSH terms
Animals, Antibodies, Antineoplastic Agents, Bicarbonates, Female, Hydrogen-Ion Concentration, Immunotherapy, Lymphocyte Activation, Mice, Inbred C57BL, T-Lymphocytes, Cell Line, Tumor, Mice, Tumor Microenvironment, CTLA-4 Antigen, Programmed Cell Death 1 Receptor

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review