Purpose: Systemic administration of recombinant interleukin (IL)-2 is used to support the expansion and persistence of adoptively transferred antigen-specific CTLs in patients with cancer. However, IL-2 also expands regulatory T cells (Treg) that in turn impair the antitumor activity of CTLs. As recombinant IL-15 is approaching clinical applications, we assessed the effects of this cytokine on the proliferation and antitumor activity of CTLs in the presence of Tregs. We used the model of adoptive transfer of Epstein-Barr virus (EBV)-CTLs, as these cells induce responses in patients with EBV-associated Hodgkin lymphoma, and Tregs are frequently abundant in these patients.
Experimental Design: Tregs were isolated from the peripheral blood of healthy donors and patients with Hodgkin lymphoma or from Hodgkin lymphoma tumors and assessed for their ability to inhibit the proliferation and antitumor activity of EBV-CTLs in the presence of IL-15 or IL-2. Specific molecular pathways activated by IL-15 were also explored.
Results: We found that in the presence of Tregs, IL-15, but not IL-2, promoted the proliferation, effector function, and resistance to apoptosis of effectors T cells and EBV-CTLs. IL-15 did not reverse or block Tregs but instead preferentially supported the proliferation of CTLs and effector T cells as compared with Tregs.
Conclusions: IL-15 selectively favors the survival, proliferation, and effector function of antigen-specific CTLs in the presence of Tregs, and thus IL-15, unlike IL-2, would have a significant impact in sustaining expansion and persistence of adoptively transferred CTLs in patients with cancer, including those infused with EBV-CTLs for treatment of EBV-associated malignancies.
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http://dx.doi.org/10.1158/1078-0432.CCR-12-2143 | DOI Listing |
BMC Plant Biol
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Zhejiang Province Key Laboratory of Plant Secondary Metabolism and Regulation, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, 310018, China.
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Department of Thoracic Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China; Key Laboratory of Precision Diagnosis and Treatment of Lung Tumors in Shandong Provincial Medicine and Health, Shandong University, Jinan, China; Key Laboratory of Basic Research and Clinical Transformation of Thoracic Tumors in Shandong Provincial Colleges and Universities, Shandong University, Jinan, China. Electronic address:
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i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; Cancer Drug Resistance Group, IPATIMUP - Institute of Molecular Pathology and Immunology, University of Porto, 4200-135 Porto, Portugal; FFUP - Faculty of Pharmacy of the University of Porto, 4050-313 Porto, Portugal. Electronic address:
Multidrug resistance (MDR) is a major challenge in cancer research. Collateral sensitizers, compounds that exploit the enhanced defense mechanisms of MDR cells as weaknesses, are a proposed strategy to overcome MDR. Our previous work reported the synthesis of two novel Isoquinolinequinone (IQQ) N-oxides that induce collateral sensitivity in MDR ABCB1-overexpressing non-small cell lung cancer (NSCLC) and colorectal cancer cells.
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