Journal Article

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

Zarogoulidis, Paul, Kioseoglou, Efrosini, Zarogoulidis, Konstantinos, Freitag, Lutz, Anestakis, Doxakis, Petanidis, Savvas, Domvri, Kalliopi, Eberhardt, Wilfried, Hohenforst-Schmidt, Wolfgang

2016

Overview

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. [Display omitted] •Blockage of autophagy increases lung cancer chemosensitivity to carboplatin.•Autophagy inhibition triggers upregulation of Foxp3+ and CD4+ TILs.•Targeting of autophagy elucidates immune T cell infiltration.•Autophagic inhibition promotes reduction in the expression of drug resistance genes.•MiR-155 functions as a novel immune system activator by promoting TILs infiltration.

• Publisher: Elsevier B.V,John Wiley & Sons, Inc,John Wiley and Sons Inc
• Subject: Adult / Aged / Aged, 80 and over / Antineoplastic Agents - pharmacology / Antineoplastic Agents - therapeutic use / Antirheumatic Agents - pharmacology / Antirheumatic Agents - therapeutic use / Apoptosis / Apoptosis - drug effects / Autophagy / Autophagy - drug effects / Cancer therapies / Carboplatin / Carboplatin - pharmacology / Carboplatin - therapeutic use / Carcinoma, Non-Small-Cell Lung - drug therapy / Carcinoma, Non-Small-Cell Lung - immunology / Carcinoma, Non-Small-Cell Lung - pathology / Carcinoma, Non-Small-Cell Lung - secondary / Caspase / Caspase-8 / CD4 antigen / CD4-Positive T-Lymphocytes - drug effects / CD4-Positive T-Lymphocytes - immunology / CD4-Positive T-Lymphocytes - pathology / CD8 antigen / Cell activation / Cell cycle / Chemoresistance / Chemosensitization / Chemotherapy / Chloroquine / Chloroquine - pharmacology / Chloroquine - therapeutic use / Consent / Drug resistance / Drug Resistance, Neoplasm - drug effects / Ethics / Foxp3 protein / Gene expression / Gene Expression Regulation, Neoplastic - drug effects / Hospitals / Humans / Immune system / Immunosuppression / Ligands / Lung - drug effects / Lung - immunology / Lung - pathology / Lung cancer / Lung Neoplasms - drug therapy / Lung Neoplasms - immunology / Lung Neoplasms - pathology / Lung Neoplasms - secondary / Lymphocytes / Lymphocytes T / Lymphocytes, Tumor-Infiltrating - drug effects / Lymphocytes, Tumor-Infiltrating - immunology / Lymphocytes, Tumor-Infiltrating - pathology / MDR1 protein / Metastases / Metastasis / MicroRNAs / MicroRNAs - genetics / MicroRNAs - immunology / Middle Aged / miR-155 / P-Glycoprotein / Patients / PD-L1 protein / Phagocytosis / Proteins / Studies / TNF-Related Apoptosis-Inducing Ligand - immunology / TRAIL / Tumor infiltrating lymphocytes / Tumor necrosis factor-TNF / Tumorigenesis