Targeting tumor-associated acidity in cancer immunotherapy

Abstract

Checkpoint inhibitors, such as cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) and programmed cell death-1 (PD-1) monoclonal antibodies have changed profoundly the treatment of melanoma, renal cell carcinoma, non-small cell lung cancer, Hodgkin lymphoma, and bladder cancer. Currently, they are tested in various tumor entities as monotherapy or in combination with chemotherapies or targeted therapies. However, only a subgroup of patients benefit from checkpoint blockade (combinations). This raises the question, which all mechanisms inhibit T cell function in the tumor environment, restricting the efficacy of these immunotherapeutic approaches. Serum activity of lactate dehydrogenase, likely reflecting the glycolytic activity of the tumor cells and thus acidity within the tumor microenvironment, turned out to be one of the strongest markers predicting response to checkpoint inhibition. In this review, we discuss the impact of tumor-associated acidity on the efficacy of T cell-mediated cancer immunotherapy and possible approaches to break this barrier.

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Fig. 1

Abbreviations

CA:

Carbonic anhydrase

CEST-MRI:

Chemical exchange saturation transfer-MRI

CTLA-4:

Cytotoxic T-lymphocyte-associated protein 4

DCA:

Dichloroacetate

DNP-MRSI:

Dynamic nuclear polarization-MRSI

MCT:

Monocarboxylate transporter

NHE:

Sodium proton exchanger

NKT cell:

Natural killer T cell

PET:

Positron emission tomography

PPI:

Proton pump inhibitor

TME:

Tumor microenvironment

Treg :

Regulatory T cells

V-ATPase:

Vacuolar-type H+-ATPase

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Contributions

Ruben Lacroix wrote the majority of the review and processed writing and suggestions by the co-authors. Elisa A Rozeman wrote the chapter “Tumor acidity as a predictive and prognostic marker for IT” and provided comments for the rest of the review. Kathrin Renner contributed considerable to the chapters “Anti-acidic interventions combined with immune therapy” and “Effects of acidity on the mmune system” and provided input for other parts. The whole was done under the supervision of and final inspection by Marina Kreutz and Christian Blank.

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Correspondence to Christian U. Blank.

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Christian U. Blank receives grants and/or research support from Novartis and BMS, and has received honoraria or consultation fees for MSD, BMS, Roche, Novartis, GSK, Pfizer and Lilly. The other authors declare that they have no conflict of interest.

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Lacroix, R., Rozeman, E.A., Kreutz, M. et al. Targeting tumor-associated acidity in cancer immunotherapy. Cancer Immunol Immunother 67, 1331–1348 (2018). https://doi.org/10.1007/s00262-018-2195-z

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Keywords

  • Cancer
  • Immune therapy
  • Checkpoint blockade
  • Acidity
  • Lactic acid
  • Metabolism