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Cited by 1,946Cancer, Hypoxia, and MetabolismImmune cells in cancerCancer Immunotherapy and Biomarkers

Inhibitory effect of tumor cell-derived lactic acid on human T cells

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Fischer, Karin, Hoffmann, Petra, Voelkl, Simon, Meidenbauer, Norbert, Ammer, Julia, Edinger, Matthias, Gottfried, Eva, Schwarz, Sabine +9 more·2007·Blood
DOI 10.1182/blood-2006-07-035972
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Abstract

A characteristic feature of tumors is high production of lactic acid due to enhanced glycolysis. Here, we show a positive correlation between lactate serum levels and tumor burden in cancer patients and examine the influence of lactic acid on immune functions in vitro. Lactic acid suppressed the proliferation and cytokine production of human cytotoxic T lymphocytes (CTLs) up to 95% and led to a 50% decrease in cytotoxic activity. A 24-hour recovery period in lactic acid–free medium restored CTL function. CTLs infiltrating lactic acid–producing multicellular tumor spheroids showed a reduced cytokine production. Pretreatment of tumor spheroids with an inhibitor of lactic acid production prevented this effect. Activated T cells themselves use glycolysis and rely on the efficient secretion of lactic acid, as its intracellular accumulation disturbs their metabolism. Export by monocarboxylate transporter-1 (MCT-1) depends on a gradient between cytoplasmic and extracellular lactic acid concentrations and consequently, blockade of MCT-1 resulted in impaired CTL function. We conclude that high lactic acid concentrations in the tumor environment block lactic acid export in T cells, thereby disturbing their metabolism and function. These findings suggest that targeting this metabolic pathway in tumors is a promising strategy to enhance tumor immunogenicity.

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Crossref · 10.1182/blood-2006-07-035972

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  • In a highly glycolytic tumor microenvironment, lactate eliminates the efficacy of immune checkpoint inhibition by modulating the balance of PD-1 expression between CD8+ T cells and Treg cells.

    “For example, accumulation of lactate derived from cancer cells impairs cytokine production and proliferation of cytotoxic T lymphocytes, whereas in the context of a highly glycolytic TME, lactate eliminates the efficacy of immune checkpoint inhibition by modulating the balance of PD-1 expression between CD8+ T cells and Treg cells [87, 88].”

    From The HIF Axes in Cancer - Angiogenesis, Metabolism and Immune-Modulation (2025) · cites this paper as [87]

    The Abstract and Discussion report that tumor-derived lactic acid suppresses CD8+ cytotoxic T-cell function. They do not address immune checkpoint inhibition or a PD-1 expression balance between CD8+ T cells and Treg cells, so they do not support the claimed effect on treatment efficacy or its proposed mechanism. (LLM, conf=0.85)

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  • 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 [83]

    The Introduction (page not supplied) says tumor cells produce lactic acid, lowering tumor-environment pH; the Discussion reports that tumor-derived lactic acid suppresses T-cell function and that an LDH inhibitor prevents this effect. The paper does not establish competition with immune cells for glucose uptake via SLC2A1/GLUT1 or attribute extracellular acidification to CA9. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Accumulation of lactate from cancer cells impairs cytokine production and proliferation of cytotoxic T lymphocytes.

    “For example, accumulation of lactate derived from cancer cells impairs cytokine production and proliferation of cytotoxic T lymphocytes, whereas in the context of a highly glycolytic TME, lactate eliminates the efficacy of immune checkpoint inhibition by modulating the balance of PD-1 expression between CD8+ T cells and Treg cells [87, 88].”

    From The HIF Axes in Cancer - Angiogenesis, Metabolism and Immune-Modulation (2025) · cites this paper as [87]

    Experimental — accuracy not yet measured

  • Higher lactate concentrations create a microenvironment that favors immune tolerance, reducing activation of dendritic cells and T cells and impairing monocyte movement.

    “Increased lactate levels promote the emergence of an immune-permissive microenvironment by attenuating dendritic and T cell activation and monocyte migration (Fischer et al., 2007; Goetze et al., 2011; Gottfried et al., 2006).”

    From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Fischer et al., 2007

  • Tumor-derived lactate can suppress CTL function directly by blocking lactate export by T cells, thus disrupting their ability to maintain glycolysis.

    “Tumor-derived lactate can also suppress CTL function directly by blocking lactate export by T cells, thus disrupting their ability to maintain glycolysis (121).”

    From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [121]

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Research works printed but not linked: 1

  1. [7]7. Talks KL, Turley H, Gatter KC, et al. The expres- sion and distribution of the hypoxia-inducible fac- tors HIF-1alpha and HIF-2alpha in normal human tissues, cancers, and tumor-associated macro- phages. Am J Pathol. 2000;157:411-421.

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Authors
Fischer, K., Hoffmann, P., Voelkl, S., Meidenbauer, N., Ammer, J., Edinger, M., Gottfried, E., Schwarz, S., Rothe, G., Hoves, S., Renner, K., Timischl, B., Mackensen, A., Kunz-Schughart, L., Andreesen, R., Krause, S. W., & Kreutz, M.
Affiliations
  • Department of Hematology and Oncology
  • Laboratory Center Bremen, Bremen, Germany
  • Institut de Génomique Fonctionnelle (FR)
  • Institute of Pathology, University of Regensburg, Regensburg, Germany;
ORCID
Venue
Blood
Publisher
American Society of Hematology
Published
2007-01-25
Volume
109
Issue
9
Pages
3812-3819
ISSN
  • 0006-4971 (ISSN-L)
  • 1528-0020
DOI
10.1182/blood-2006-07-035972
OpenAlex
W2060878129
Cited by
1,946
References
44
Citations by year
2026: 172 · 2025: 167 · 2024: 166 · 2023: 188 · 2022: 207 · 2021: 227 · 2020: 165 · 2019: 124 · 2018: 95 · 2017: 99 · 2016: 80 · 2015: 52 · 2014: 47 · 2013: 42 · 2012: 32
FWCI
7.05
Type
journal article
Language
en
Open access
Locations
  • Blood (publishedVersion)
  • PubMed (publishedVersion)
  • University of Regensburg Publication Server (University of Regensburg) (submittedVersion)
Funders
Deutsche Forschungsgemeinschaft
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Keywords
lactic acid, tumor microenvironment, cytotoxic T lymphocytes, MCT1, tumor immunogenicity, tumor burden, cytokine production, T cell proliferation, tumor spheroids, cancer immunotherapy
MeSH terms
Biological Transport, Dose-Response Relationship, Drug, Female, Glycolysis, Humans, Lymphocyte Activation, Male, Neoplasms, T-Lymphocytes, Tumor Cells, Cultured, Oncogene Proteins, Cell Cycle Proteins, Spheroids, Cellular, Lactic Acid, Cell Proliferation

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