Journal Article

Kras-driven intratumoral heterogeneity triggers infiltration of M2 polarized macrophages via the circHIPK3/PTK2 immunosuppressive circuit

Charalampidis, Charalampos, Bai, Chong, Tsavlis, Drosos, Zarogoulidis, Paul, Matthaios, Dimitris, Freitag, Lutz, Anestakis, Doxakis, Petanidis, Savvas, Huang, Haidong, Domvri, Kalliopi, Katopodi, Theodora, Hohenforst-Schmidt, Wolfgang, Porpodis, Konstantinos

2021

Overview

Intratumoral heterogeneity in lung cancer is essential for evasion of immune surveillance by tumor cells and establishment of immunosuppression. Gathering data reveal that circular RNAs (circRNAs), play a role in the pathogenesis and progression of lung cancer. Particularly Kras-driven circRNA signaling triggers infiltration of myeloid-associated tumor macrophages in lung tumor microenvironment thus establishing immune deregulation, and immunosuppression but the exact pathogenic mechanism is still unknown. In this study, we investigate the role of oncogenic Kras signaling in circRNA-related immunosuppression and its involvement in tumoral chemoresistance. The expression pattern of circRNAs HIPK3 and PTK2 was determined using quantitative polymerase chain reaction (qPCR) in lung cancer patient samples and cell lines. Apoptosis was analyzed by Annexin V/PI staining and FACS detection. M2 macrophage polarization and MDSC subset analysis (Gr1 − /CD11b − , Gr1 − /CD11b + ) were determined by flow cytometry. Tumor growth and metastatic potential were determined in vivo in C57BL/6 mice. Findings reveal intra-epithelial CD163 + /CD206 + M2 macrophages to drive Kras immunosuppressive chemoresistance through myeloid differentiation. In particular, monocytic MDSC subsets Gr1 − /CD11b − , Gr1 − /CD11b + triggered an M2-dependent immune response, creating an immunosuppressive tumor-promoting network via circHIPK3/PTK2 enrichment. Specifically, upregulation of exosomal cicHIPK3/PTK2 expression prompted Kras-driven intratumoral heterogeneity and guided lymph node metastasis in C57BL/6 mice. Consequent co-inhibition of circPTK2/M2 macrophage signaling suppressed lung tumor growth along with metastatic potential and prolonged survival in vivo . Taken together, these results demonstrate the key role of myeloid-associated macrophages in sustaining lung immunosuppressive neoplasia through circRNA regulation and represent a potential therapeutic target for clinical intervention in metastatic lung cancer.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/250 / 631/67 / A549 Cells / Animals / Annexin V / Apoptosis / Carcinoma, Non-Small-Cell Lung - metabolism / CD11b antigen / CD163 antigen / CD4-Positive T-Lymphocytes - cytology / Chemoresistance / Deregulation / Disease Progression / Disease-Free Survival / Flow cytometry / Gene Expression Regulation, Neoplastic / Heterogeneity / Humanities and Social Sciences / Humans / Immune response / Immunosuppression / Immunosuppression Therapy / Immunosuppressive Agents - therapeutic use / Immunosurveillance / Infiltration / K-Ras protein / Lung cancer / Lung Neoplasms - metabolism / Lymph nodes / Macrophage Activation / Macrophages / Macrophages - metabolism / Male / Metastases / Metastasis / Mice / Mice, Inbred C57BL / Monocytes / multidisciplinary / Mutation / Neoplasm Metastasis / Polymerase chain reaction / RNA, Circular - metabolism / RNA, Small Interfering - metabolism / Science / Science (multidisciplinary) / Signal Transduction / Tumor cell lines / Tumor cells / Tumor microenvironment / Tumor Microenvironment - immunology / Tumors