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Immunotherapy on acid: opportunities and challenges

European Journal of Clinical Nutrition volume 74, pages 3–6 (2020)Cite this article

Acidosis and hypoxia in the tumor microenvironment are immunosuppressive, and therapeutic approaches are emerging to mitigate their effects and improve immune therapy. While immunotherapy has shown great promise, it is limited by numerous immunosuppressive mechanisms in the microenvironment, such as checkpoints, inhibitory cytokines, and suppressor cells. A less well understood, but emerging, suppressive mechanism is the physiological microenvironment of tumors, specifically hypoxia and acidosis. Due to imbalances between vascularity and cellular growth patterns, sub-regions of tumors (habitats) contain microenvironments that harbor these metabolic stressors. Hypoxia and acidity have an influence on almost all immune cell components, and negatively affect responses to current immunotherapies. There is emerging evidence that these stressors can be directly or indirectly targeted to improve immune therapy response, and that such interventions will undoubtedly provide benefit, especially if applied in a biomarker-driven adaptive manner.

Acidosis is one of the most frequent characteristics of solid tumors as a result of metabolic switch to glycolysis and rapid growth with poor vascular support [3]. Less is known regarding the effect of acidic microenvironment on immune cells when compared with hypoxia despite its observation in many cancer types [4]. In isolated cases, TDAG8 has been implicated, but this is not general (personal observations). It is known that lactate can potently exacerbate the effects of low pH and, in some cases, can mediate effects without changes in pH. In general the effects of acidity on immune function include changes in macrophage and helper T-cell polarities toward pro-inflammatory phenotypes, induction of anergy in CD8 + Teff cells, and increased antigen presentation capacity of DCs.

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Fig. 1: Effect of hypoxia and acidosis on immune function.

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Funding

This article is published as part of a supplement sponsored by NuOmix-Research k.s. The conference was financially supported by Protina Pharmazeutische GmbH, Germany and Sirius Pharma, Germany, and organized by NuOmix-Research k.s. Neither company had any role in writing of the paper.

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Authors and Affiliations

  1. Department of Cancer Physiology, H. Lee Moffitt Cancer Center, Tampa, FL, USA

    Sultan Damgaci, Pedro M. Enriquez-Navas, Robert J. Gillies & Arig Ibrahim-Hashim

  2. Institute of Biomedical Engineering, Bogazici University, Istanbul, Turkey

    Sultan Damgaci & Albert Guvenis

  3. Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL, USA

    Shari Pilon-Thomas

  4. Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA

    Shari Pilon-Thomas

  5. Department of Radiology, H. Lee Moffitt Cancer Center, Tampa, FL, USA

    Robert J. Gillies

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Correspondence to Arig Ibrahim-Hashim.

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Conflict of interest

SD and AI-H received grant support from Helix Biopharma. RJG received grant support from Helix Biopharma & Healthmyne, and NIH Small Business Innovation Research (SBIR) with Healthmyne, Inc; RJG also holds stock HealthMyne, Inc (H-M), which is a commercial quantitative PACS system for reading and analysis of radiographic scans, and held stock in Helix until 2017. SP-T received grant support from the American Cancer Society.

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Damgaci, S., Enriquez-Navas, P.M., Pilon-Thomas, S. et al. Immunotherapy on acid: opportunities and challenges. Eur J Clin Nutr 74 (Suppl 1), 3–6 (2020). https://doi.org/10.1038/s41430-020-0683-7

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