Improved anti-tumor vaccination activity of necroptotic cells lacking ATG16L1-dependent unconventional autophagy

Immunogenic forms of tumor cell death can induce effective anti-cancer immune responses, but the molecular mechanisms that regulate the immunogenic potential of cell suicide and how they shape anti-tumor immunity in vivo are issues that remain to be fully elucidated. Here we show that absence of unconventional autophagy mediated by the WD40 domain (WDD) of ATG16L1 increases the anti-tumor vaccinating capacity of dying cells. Necroptotic mouse carcinoma MC38 cells lacking the WDD fail to mount a concomitant unconventional autophagic response and exhibit superior vaccinating capacity against MC38 tumors inoculated afterwards. The mutant strain secretes higher levels of ATP during cell demise, whereas other Damage-Associated Molecular Patterns (DAMPs) remain unaffected. The vaccinating effect is accompanied by increased tumor immune infiltration, depends on secreted ATP and requires T cells. These results indicate that suppression of ATG16L1-mediated unconventional autophagy during tumor cell death improves anti-tumor immunity, and identify this process as a potential therapeutic target to enhance the immune contribution to control tumor development.