Unit:
Specialty Molecular Biomedicine Mechanisms of Disease, Molecular and Cellular Therapies, and BioinnovationLibrary of the School of Health Sciences
Author:
Papadopoulou Miranta
Supervisors info:
Βεργίνης Παναγιώτης, Ερευνητής Γ΄, ΙΙΒΕΑΑ
Κλινάκης Απόστολος, Ερευνητής Α΄, ΙΙΒΕΑΑ
Μπούμπας Δημήτριος, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Original Title:
Delineation of the role of Cancer-associated fibroblast autophagy and phagocytic contexture in shaping tumor development and anti-tumor immunity
Translated title:
Delineation of the role of Cancer-associated fibroblast autophagy and phagocytic contexture in shaping tumor development and anti-tumor immunity
Summary:
Tumor microenvironment (TME) is considered crucial promoter of tumorigenesis, while it plays essential role in the regulation of immune response inside the tumors. The highly hypoxic, nutrient- deficient and rich in inflammatory factors TME activates several stress response pathways in cells, in order to enable their adaptation to these abnormal conditions. Autophagy is a fundamental catabolic pathway which is induced as a response to these conditions inside the cells while it is considered as a cardinal feature of many tumors. Autophagy can have either tumor promoting or tumor suppressing functions in cancer and this dual role has been studied extensively. Cancer- associated fibroblasts (CAFs) are the predominant non-hematopoietic cell population of TME, characterized by the expression of α-smooth muscle actin (αSMA) in their activated stage. CAFs are known for their tumor promoting functions and their critical implication in the regulation of anti- tumor immunity. However, less are known about the underlying mechanisms driving CAF-related functions. The process of autophagy in CAFs has been studied in a limited extent providing evidence for its tumor promoting function. Nevertheless, its role in shaping the anti-tumor immune response remains elusive.
Herein, we aimed to investigate the potential regulatory role of CAFs autophagy in tumor progression and anti-tumor immune response. We used αSMA-RFP transgenic mice that have a DsRed fluorescent reporter in αSMA-expressing cells, in order to identify the unique morphology and the spatial location of CAFs in αSMA-RFP mouse melanoma tumors. CAFs were found scattered among the cancer cells as well as in the periphery creating a “barrier”. Autophagy was activated in fibroblasts cultured under conditions mimicking the TME providing evidence for upregulation of autophagy in CAFs. The specific depletion of autophagy in CAFs resulted in reduced tumor growth as indicated by melanoma tumor inoculation experiments in αSMA- creAtg5fl/fl transgenic mice, highlighting the considerable role of CAFs autophagy in tumor progression. Despite this, the analysis of the infiltrating immune populations was characterized by great heterogeneity which may indicate that the immune alterations were a secondary phenomenon.
Collectively, our data bring into focus CAFs as an important cell population characterized by upregulated autophagy, with essential role in the regulation of tumor progression. Elucidation of this process would provide a great mechanistic insight of how CAFs influence tumor immune response and ultimately lead to development of more efficacious immunotherapeutic approaches.
Main subject category:
Health Sciences
Keywords:
Autophagy, Fibroblasts, Cancer, Immunity, Immunotherapy
