Interplay between inflammation and autophagy in dendritic cells during cancer immune evasion

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Cancer inflammation can favour efficient tumour rejection or development i.e via evasion from immune surveillance. Despite recent advances in understanding the immuno-regulatory and anti-inflammatory mechanisms of cancer immune evasion, it is important to elucidate the pro-inflammatory machinery behind this process towards combinatorial therapy against inflammatory cancer. Dendritic cells (DCs) are central actors for anti-tumour immune responses. They stand out in the uptake of proteins from tumour cells, followed by lysosomal processing and presentation of tumour-associated antigens to lymphocytes to prime their activity against tumours. Antigen-presentation in DCs was suggested to be regulated by autophagy, a lysosomal pathway degrading intracellular cargos for their re-use to maintain cellular homeostasis and functions. However, autophagy role in DC function within inflammatory tumour microenvironment (TME) in vivo remains largely unexplored. How autophagy in DCs affects their function against cancer, and how inflammatory TME affects autophagy in DCs remain 2 sine-qua-non questions with no clear answer so far. Whence, I will endeavour to address these questions in well-established tumour models by joining my strong background in autophagy and know-how in DC biology with the expertise of the host lab on lymphocytes in tumour inflammation. Promising observations from preliminary data I generated suggest that inflammatory tumours restrain autophagy in DCs to evade immune surveillance, which prompted me to build the hypothesis behind this project. I intend to test this hypothesis by employing state-of-the-art murine melanoma models mimicking inflammatory "hot" and non-inflammatory "cold" tumours engrafted in bi-transgenic mice bearing autophagy-deficient DCs. The expected outcomes of this project will tackle the central issue of inflammatory cancer immune evasion, whose cause and mechanism are still obscure despite their importance for immunotherapies efficiency.