Autophagy inhibition upregulates CD4+ tumor infiltrating lymphocyte expression via miR‐155 regulation and TRAIL activation

Molecular Oncology - Tập 10 - Trang 1516-1531 - 2016
Paul Zarogoulidis1, Savvas Petanidis2, Kalliopi Domvri1, Efrosini Kioseoglou2, Doxakis Anestakis3,4, Lutz Freitag5, Konstantinos Zarogoulidis1, Wolfgang Hohenforst-Schmidt6, Wilfried Eberhardt7
1Pulmonary Department-Oncology Unit, “G. Papanikolaou” General Hospital, Aristotle University of Thessaloniki, Thessaloniki, 57010, Greece
2Department of Chemical Engineering, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece
3Department of Medicine, Laboratory of General Biology, Aristotle University of Thessaloniki, Thessaloniki, 54124, Greece
4Department of Medicine, Laboratory of Forensic Medicine and Toxicology, Aristotle University of Thessaloniki, 54124, Greece
5Department of Interventional Pneumology, Ruhrlandklinik, University Hospital Essen, University of Essen-Duisburg, Tueschener Weg 40, 45239, Essen, Germany
6Medical Clinic I, ”Fuerth” Hospital, University of Erlangen, 91054, Fuerth, Germany
7Division of Thoracic Oncology, Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, 45122, Essen, Germany

Tóm tắt

AbstractChemoresistance is a major challenge in lung cancer treatment. Recent findings have revealed that autophagic mechanism contributes significantly to immunosuppressive related chemoresistance. For that reason, targeting autophagy‐related immunosuppression is an important approach to reverse tumor drug resistance. In this study, we report for the first time that autophagy inhibition triggers upregulation of CD4+, Foxp3+ tumor infiltrating lymphocytes in late metastatic lung cancer tissues. Furthermore, autophagy blockage induces chemosensitization to carboplatin, immune activation and cell cycle arrest. This induction correlated with reduction in expression of drug resistance genes MDR1, MRP1, ABCG2 and ABCC2 along with decreased expression of PD‐L1 which is associated with severe dysfunction of tumor specific CD8+ T cells. Furthermore, experiments revealed that co‐treatment of carboplatin and autophagy inhibitor chloroquine increased lung tissue infiltration by CD4+, FoxP3+ lymphocytes and antigen‐specific immune activation. Subsequent ex vivo experiments showed the activation of carboplatin related TRAIL‐dependent apoptosis through caspase 8 and a synergistic role of miR‐155 in lung tissue infiltration by CD4+, and FoxP3+ lymphocytes. Overall, our results indicate that autophagy blockage increases lung cancer chemosensitivity to carboplatin, but also reveal that miR‐155 functions as a novel immune system activator by promoting TILs infiltration. These results indicate that targeting of autophagy can prevent cancer related immunosuppression and elucidate immune cell infiltration in tumor microenvironment thus representing a potential therapeutic strategy to inhibit lung cancer progression and metastasis.

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Molecular Oncology

Tập 10

1516-1531

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