Necroptotic-susceptible dendritic cells exhibit enhanced antitumor activities in mice

Abstract

Introduction: Priming of tumor-specific T cells is a key to antitumor immune response and inflammation, in turn, is crucial for proper T-cell activation. As antigen-presenting cells can activate T cells, dendritic cells (DCs) loaded with tumor antigens have been used as immunotherapeutics against certain cancer in humans but their efficacy is modest. Necroptosis is a form of programmed cell death that results in the release of inflammatory contents. We previously generated mice with DC deficiency in a negative regulator of necroptosis, Fas-associated death domain (FADD), and found that these mice suffer from systemic inflammation due to necroptotic DCs. We hypothesize that FADD-deficient DCs could serve as a better vaccine than wild-type (WT) DCs against tumors. Materials and Methods: FADD-deficient and WT mouse DCs loaded with the relevant tumor peptide were injected onto mice before or after the syngeneic tumor challenge. DC vaccinations were repeated two more times and anti-PD-1 antibodies were coinjected in some experiments. Tumor sizes were measured by caliper, and the percentages of tumor-free mice or mice survived were examined over time. The cytometric analysis was carried out to analyze various immune populations. Results: In two separate tumor models, we find that mice receiving FADD-deficient DCs as vaccine rejected tumors significantly better than those receiving a WT DC vaccine. Tumor growth was severely hampered, and survival extended in these mice. More activated CD8 T cells together with elevated cytokines were observed in mice receiving the FADD-deficient DC vaccine. Furthermore, we observed these effects were potent enough to protect against tumor challenge postinjection and can work in conjunction with anti-PD-1 antibodies to reduce the tumor growth. Conclusions: Necroptotic-susceptible DCs are better antitumor vaccines than WT DCs in mice. Our findings suggest that necroptosis-driven inflammation by DCs may be a novel avenue to generating a strong adaptive antitumor response in the clinical setting.