Autophagy inhibition upregulates CD4+tumor infiltrating lymphocyte expression via miR-155 regulation and TRAIL activation.
Chemoresistance 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.
Pulmonary Department-Oncology Unit, "G. Papanikolaou" General Hospital, Aristotle University of Thessaloniki, Thessaloniki, 57010, Greece.
Paul
P
Zarogoulidis
Department of Chemical Engineering, Aristotle University of Thessaloniki, Thessaloniki, 54124, Greece. Electronic address: spetanid@auth.gr.
Savvas
S
Petanidis
Pulmonary Department-Oncology Unit, "G. Papanikolaou" General Hospital, Aristotle University of Thessaloniki, Thessaloniki, 57010, Greece.
Kalliopi
K
Domvri
Department of Chemical Engineering, Aristotle University of Thessaloniki, Thessaloniki, 54124, Greece.
Efrosini
E
Kioseoglou
Department of Medicine, Laboratory of General Biology, Aristotle University of Thessaloniki, Thessaloniki, 54124, Greece; Department of Medicine, Laboratory of Forensic Medicine and Toxicology, Aristotle University of Thessaloniki, 54124, Greece.
Doxakis
D
Anestakis
Department of Interventional Pneumology, Ruhrlandklinik, University Hospital Essen, University of Essen-Duisburg, Tueschener Weg 40, 45239, Essen, Germany.
Lutz
L
Freitag
Pulmonary Department-Oncology Unit, "G. Papanikolaou" General Hospital, Aristotle University of Thessaloniki, Thessaloniki, 57010, Greece.
Konstantinos
K
Zarogoulidis
Medical Clinic I, "Fuerth" Hospital, University of Erlangen, 91054, Fuerth, Germany.
Wolfgang
W
Hohenforst-Schmidt
Division of Thoracic Oncology, Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, 45122, Essen, Germany.
Wilfried
W
Eberhardt
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D018501:Antirheumatic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D016190:Carboplatin / Q000494:pharmacology / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology / Q000556:secondary; D002738:Chloroquine / Q000494:pharmacology / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008168:Lung / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology / Q000556:secondary; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics* / Q000276:immunology; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000276:immunology*
C000715087:ABCC2 protein, human; D000970:Antineoplastic Agents; D018501:Antirheumatic Agents; C524942:MIRN155 microRNA, human; D035683:MicroRNAs; D000089762:Multidrug Resistance-Associated Protein 2; D053221:TNF-Related Apoptosis-Inducing Ligand; D002738:Chloroquine; D016190:Carboplatin
Chemoresistance; Lung cancer; TRAIL; Tumor infiltrating lymphocytes; miR-155
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