Supervisors info:
Παναγιώτης Βεργίνης, Ερευνητής Γ', Ίδρυμα Ιατροβιολογικών Ερευνών Ακαδημίας Αθηνών
Δημήτριος Μπούμπας, Καθηγητής, Ιατρική, Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών
Αριστείδης Ηλιόπουλος, Καθηγητής, Ιατρική, Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών
Summary:
The advent of immune checkpoint inhibitors (ICI) has revolutionized cancer therapeutics, yet a sizable portion of patients is associated with low response rates. A major impediment in the effectiveness of ICI immunotherapy is the hypoxic conditions of the tumor microenvironment (TME). A mechanism that is induced by hypoxia and represents a cardinal feature of most tumors is autophagy. Even though most studies have focused on the role of autophagy in tumor cells, the involvement of autophagy in the stromal compartment, and in particular in cancer-associated fibroblasts (CAFs), has been investigated to a limited extend. CAFs represent a highly heterogeneous yet abundant cell population of the TME, quite resistant to chemo/radiotherapy. Although their tumor-promoting function is acknowledged, their role in shaping the anti-tumor immune response remains elusive.
Herein, we demonstrated that α-SMA+CAFs were enriched in the TME of B16-F10 inoculated C57BL/6 mouse melanoma, while a α-SMA+ population was detected in circulation in later tumor stages. After validating that the phosphorylated levels of AKT, mTOR and S6 were downregulated upon tumor progression in vivo, we observed that tumor explants supernatant (TES)-treated fibroblastic cells exhibited deregulated autophagy compared to untreated cells in vitro. The phosphorylated levels of PI3K/AKT/mTOR pathway were also decreased upon administration of immune checkpoint inhibitor, anti-PD-L1 in vivo. To assess the functional role of autophagy in CAFs, we generated for the first time the transgenic mice α-SMA-Cre Atg5fl/fl; the ablation of autophagy from CAFs led to earlier tumor development, with altered frequencies of tumor infiltrating immune cells (P=0.064), MDSCs (P=0.044) and α-SMA+ CAFs (P=0.059) in the TME.
Collectively, our data bring into focus CAFs as an important cell population, characterized by enhanced autophagy, yet deregulated. Also, upon anti-PD-L1 administration, autophagy is enhanced in CAFs as tumor progresses. Elucidation of how these processes unfold will provide a better mechanistic insight of how CAFs influence tumor immune response and ultimately lead to development of more efficacious immunotherapeutic approaches.
Keywords:
Autophagy, CAFs, Immunotherapy, Melanoma
