|Keywords:||Autophagy; Cancer-associated fibroblasts; Immune regulation; inflammatory cytokines; Melanoma|
|Full text PDF:||http://arks.princeton.edu/ark:/88435/dsp01d217qr92p|
Through degrading bulk cytoplasmic materials into intermediate building blocks, autophagy refuels metabolism and maintains homeostasis under starvation and stress conditions. The context-dependent role of autophagy in cancer cells during tumorigenesis and tumor progression has been explored over the past decade; however, studies of autophagy in relation to the tumor microenvironment are still lacking. In this study, we investigated the role of autophagy in cancer-associated fibroblasts (CAFs), a major component of the microenvironment that is important for the growth and development of cutaneous melanoma. Analysis of clinical biopsies revealed high levels of autophagy in fibroblasts that surrounded melanoma cells, but not in the non-tumor adjacent area. Fibroblasts co-cultured with melanoma cell lines, but not melanocytes, also showed increased autophagic flux, which requires transforming growth factor beta (TGF-β) signaling. Knocking down autophagy-related (ATG) genes ATG5 or ATG7 in fibroblasts did not impair their proliferation in vitro, but inhibited the growth of co-engrafted melanoma cells in vivo. Further, by introducing intradermal melanoma allografts into mice that harbored fibroblast-specific Atg7 deletion, we observed remarkable tumor growth retardation. In order to mimic anti-autophagy therapy for patients, we generated mice in which Atg7 is conditionally depleted in their entire bodies, and found significant tumor growth suppression. Atg7 knockout mice contained elevated plasma levels of pro-inflammatory cytokines including IFNγ, CXCL10, CXCL9, RANTES, and MCP-1. Atg7 knockout mice further showed increase of innate immune cells such as natural killer cells, dendritic cells and macrophages in the peripheral tissues, and increased CD8+ cytotoxic T cells infiltrated into the tumors. By inhibiting Th1-type cytokines/chemokines with atorvastatin, we rescued the tumor growth in systemic Atg7 knockout mice and observed reduction in the levels of tumor-infiltrating CD8+ T cells. Taken together, our data show that through modulating the tumor microenvironment, stromal autophagy inhibits pro-inflammatory chemokine production and protects cancer cells from immune surveillance. Our findings indicate that stromal autophagy may represent a valuable therapeutic target that might benefit a broad range of cancer types with better prognosis and less systemic toxicity. Advisors/Committee Members: Coller, Hilary A (advisor).