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Fischbeck, A. ; Ruehland, S.* ; Ettinger, A. ; Paetzold, K. ; Masouris, I. ; Nößner, E. ; Mendler, A.N.

Tumor lactic acidosis: Protecting tumor by inhibiting cytotoxic activity through motility arrest and bioenergetic silencing.

Front. Oncol. 10:589434 (2020)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
Adoptive T cell therapy (ACT) is highly effective in the treatment of hematologic malignancies, but shows limited success in solid tumors. Inactivation of T cells in the tumor milieu is a major hurdle to a wider application of ACT. Cytotoxicity is the most relevant activity for tumor eradication. Here, we document that cytotoxic T cells (CTL) in lactic acidosis exhibited strongly reduced tumor cell killing, which could be compensated partly by increasing the CTL to tumor cell ratio. Lactic acid intervened at multiple steps of the killing process. Lactic acid repressed the number of CTL that performed lytic granule exocytosis (degranulation) in tumor cell co-culture, and, additionally impaired the quality of the response, as judged by the reduced intensity of degranulation and lower secretion of cytotoxins (perforin, granzyme B, granzyme A). CTL in lactic acid switched to a low bioenergetic profile with an inability to metabolize glucose efficiently. They responded to anti-CD3 stimulation poorly with less extracellular acidification rate (ECAR). This might explain their repressed granule exocytosis activity. Using live cell imaging, we show that CTL in lactic acid have reduced motility, resulting in lower field coverage. Many CTL in lactic acidosis did not make contact with tumor cells; however, those which made contact, adhered to the tumor cell much longer than a CTL in normal medium. Reduced motility together with prolonged contact duration hinders serial killing, a defining feature of killing potency, but also locally confines cytotoxic activity, which helps to reduce the risk of collateral organ damage. These activities define lactic acid as a major signaling molecule able to orchestrate the spatial distribution of CTL inside inflamed tissue, such as cancer, as well as moderating their functional response. Lactic acid intervention and strategies to improve T cell metabolic fitness hold promise to improve the clinical efficacy of T cell–based cancer immunotherapy.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Cytolytic T Cells ; Degranulation ; Glycolytic State ; Immunotherapy ; Killing Potency ; Serial Killing ; T Cell Metabolism; Cd8(+) T-cells; Immune Suppression; Extracellular Ph; Cancer; Lactate; Therapy; Acidity; Assay; Microenvironment; Immunotherapy
ISSN (print) / ISBN 2234-943X
e-ISSN 2234-943X
Zeitschrift Frontiers in Oncology
Quellenangaben Band: 10, Heft: , Seiten: , Artikelnummer: 589434 Supplement: ,
Verlag Frontiers
Verlagsort Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) CF Immunoanalytics (IMA)
Institute of Epigenetics and Stem Cells (IES)
Institute of Molecular Immunology (IMI)
Förderungen Erich & Gertrud Roggenbuck Stiftung
Deutsche Krebshilfe