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, Fasassociated death domain (FADD), and found that these mice suffer from systemic inflammation due to necroptotic DCs. We hypothesize that FADDdeficient 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 FADDdeficient 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

Necroptosis-related lncRNAs signature predicts prognosis and influences immune microenvironment in patients with colon adenocarcinoma

“…Traditional anticancer drugs are currently being developed to target relevant steps in the necroptosis pathway to promote or inhibit necroptosis signaling in tumor cells [16][17][18][19]. Several studies have reported that the activation of necroptotic cell death in tumors could increase DC activation and T cell in ltration, which synergistically act with immune check-point inhibitors to enhance antitumor e ciency that promotes long-lasting tumor clearance [20][21][22][23].…”

“…FADD is a negative regulator of necroptosis. A higher number of activated CD8 + T cells and elevated levels of cytokines were observed in mice injected with the FADD-de cient DC vaccine; thus, FADD can be used to reduce tumor growth in combination with anti-PD-1 antibodies [23]. Staining of cholangiocarcinoma tissues showed that, contrary to MLKL, pMLKL-positive samples were signi cantly positively correlated with favorable immune characteristics within the tumor microenvironment (that is, high abundance of CD8 + T cell in ltration) and high PD-L1 expression, and patients with high pMLKL and PD-L1 expression showed longer OS [59].…”

“…Additionally, an increasing number of studies have shown that necroptosis and tumor immunity have a close relationship. Targeting the necroptosis pathway can not only improve the antitumor immune response of T cells in immunotherapy but also regulate the proportion of various immune in ltrating cells in the tumor microenvironment [20][21][22][23]. These ndings suggest that targeting necroptosis may be a promising antitumor strategy.…”

Targeting novel regulated cell death: Ferroptosis, pyroptosis and necroptosis in anti‐PD‐1/PD‐L1 cancer immunotherapy

“…123 Another study elegantly demonstrates that necroptosis-driven inflammation through DCs works in combination with anti-PD-1 antibodies to inhibit the proliferation of melanoma. 124 Similarly, in osteosarcoma, TNF-α-loaded liposomes induced ICD in tumour cells, leading to TNF-α-triggered necrosis, tumour-specific antigen release, enhanced DC activation, and T cell infiltration when combined with anti-PD-1/PD-L1 therapy. 125 Various stresses regulate PD-L1 expression, promoting cancer progression and impacting patient survival rates.…”

“…This small molecule‐induced Z‐DNA turnover activated ZBP1, culminating in RIPK3‐mediated necroptosis and immune system engagement against the tumour 123 . Another study elegantly demonstrates that necroptosis‐driven inflammation through DCs works in combination with anti‐PD‐1 antibodies to inhibit the proliferation of melanoma 124 . Similarly, in osteosarcoma, TNF‐α‐loaded liposomes induced ICD in tumour cells, leading to TNF‐α‐triggered necrosis, tumour‐specific antigen release, enhanced DC activation, and T cell infiltration when combined with anti‐PD‐1/PD‐L1 therapy 125 …”