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.
Highlights
Several lines of evidence suggest that T-cell immunity may play a role in controlling tumor development
Similar data were obtained using CD3þ T cells from healthy donors or Ag-specific CD8þ T lymphocytes from patients with melanoma, suggesting this is a more general response of T cells to unfavorable pH conditions rather than a specific TIL feature (Supplementary Fig. S2)
IL-2 secretion in response to mitogenic stimuli, a feature typically tested for assessing T-cell anergy [24], was strongly affected in TILs maintained for 3 days at an acidic pH (Fig. 2A)
Summary
Several lines of evidence suggest that T-cell immunity may play a role in controlling tumor development. Tumor-infiltrating T lymphocytes (TIL) with an effector/memory phenotype are associated with a more favorable prognosis in patients with cancer [1] and mediate tumor regression when adoptively transferred after ex vivo activation [2]. TILs are reported to acquire functional defects at the tumor site and enter a state of reversible anergy, mostly attributed to subop-. Authors' Affiliations: 1Cellular Immunology Unit, 2Immuno-biotherapy of Melanoma and Solid Tumors, San Raffaele Scientific Institute; 3Unit of Immunotherapy of Human Tumors, 4Melanoma and Sarcoma Unit, Fondazione IRCCS Istituto Nazionale dei Tumori; 5Universita Vita-Salute San Raffaele, Milan; 6Department of Therapeutic Research and Medicines Evaluation, Unit of Antitumor Drugs, Istituto Superiore di Sanita, Rome, Italy; and 7Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institute, Stockholm, Sweden. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
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