Modulation of microenvironment acidity reverses anergy in human and murine tumor-infiltrating T lymphocytes

Arianna Calcinotto, Paola Filipazzi, Matteo Grioni, Manuela Iero, Angelo De Milito, Alessia Ricupito, Agata Cova, Rossella Canese, Elena Jachetti, Monica Rossetti, Veronica Huber, Giorgio Parmiani, Luca Generoso, Mario Santinami, Martina Borghi, Stefano Fais, Matteo Bellone, Licia Rivoltini

Research output: Contribution to journalArticle

Abstract

Stimulating the effector functions of tumor-infiltrating T lymphocytes (TIL) in primary and metastatic tumors could improve active and adoptive T-cell therapies for cancer. Abnormal glycolysis, high lactic acid production, proton accumulation, and a reversed intra-extracellular pH gradient are thought to help render tumor microenvironments hostile to roving immune cells. However, there is little knowledge about how acidic microenvironments affect T-cell immunity. Here, we report that lowering the environmental pH to values that characterize tumor masses (pH 6-6.5) was sufficient to establish an anergic state in human and mouse tumor-specific CD8 + T lymphocytes. This state was characterized by impairment of cytolytic activity and cytokine secretion, reduced expression of IL-2Rα (CD25) and T-cell receptors (TCR), and diminished activation of STAT5 and extracellular signal-regulated kinase (ERK) after TCR activation. In contrast, buffering pH at physiologic values completely restored all these metrics of T-cell function. Systemic treatment of B16-OVA-bearing mice with proton pump inhibitors (PPI) significantly increased the therapeutic efficacy of both active and adoptive immunotherapy. Our findings show that acidification of the tumor microenvironment acts as mechanism of immune escape. Furthermore, they illustrate the potential of PPIs to safely correct T-cell dysfunction and improve the efficacy of T-cell-based cancer treatments.

Original languageEnglish
Pages (from-to)2746-2756
Number of pages11
JournalCancer Research
Volume72
Issue number11
DOIs
Publication statusPublished - Jun 1 2012

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Tumor-Infiltrating Lymphocytes
T-Lymphocytes
Tumor Microenvironment
Neoplasms
T-Cell Antigen Receptor
Adoptive Immunotherapy
Active Immunotherapy
Proton-Motive Force
Proton Pump Inhibitors
Extracellular Signal-Regulated MAP Kinases
Glycolysis
Cell- and Tissue-Based Therapy
Protons
Immunity
Lactic Acid
Therapeutics
Cytokines

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Modulation of microenvironment acidity reverses anergy in human and murine tumor-infiltrating T lymphocytes. / Calcinotto, Arianna; Filipazzi, Paola; Grioni, Matteo; Iero, Manuela; De Milito, Angelo; Ricupito, Alessia; Cova, Agata; Canese, Rossella; Jachetti, Elena; Rossetti, Monica; Huber, Veronica; Parmiani, Giorgio; Generoso, Luca; Santinami, Mario; Borghi, Martina; Fais, Stefano; Bellone, Matteo; Rivoltini, Licia.

In: Cancer Research, Vol. 72, No. 11, 01.06.2012, p. 2746-2756.

Research output: Contribution to journalArticle

Calcinotto, A, Filipazzi, P, Grioni, M, Iero, M, De Milito, A, Ricupito, A, Cova, A, Canese, R, Jachetti, E, Rossetti, M, Huber, V, Parmiani, G, Generoso, L, Santinami, M, Borghi, M, Fais, S, Bellone, M & Rivoltini, L 2012, 'Modulation of microenvironment acidity reverses anergy in human and murine tumor-infiltrating T lymphocytes', Cancer Research, vol. 72, no. 11, pp. 2746-2756. https://doi.org/10.1158/0008-5472.CAN-11-1272
Calcinotto, Arianna ; Filipazzi, Paola ; Grioni, Matteo ; Iero, Manuela ; De Milito, Angelo ; Ricupito, Alessia ; Cova, Agata ; Canese, Rossella ; Jachetti, Elena ; Rossetti, Monica ; Huber, Veronica ; Parmiani, Giorgio ; Generoso, Luca ; Santinami, Mario ; Borghi, Martina ; Fais, Stefano ; Bellone, Matteo ; Rivoltini, Licia. / Modulation of microenvironment acidity reverses anergy in human and murine tumor-infiltrating T lymphocytes. In: Cancer Research. 2012 ; Vol. 72, No. 11. pp. 2746-2756.
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AU - Iero, Manuela

AU - De Milito, Angelo

AU - Ricupito, Alessia

AU - Cova, Agata

AU - Canese, Rossella

AU - Jachetti, Elena

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AU - Parmiani, Giorgio

AU - Generoso, Luca

AU - Santinami, Mario

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