Immunogenic cell death (ICD) occurs when a dying cell releases
cytokines and damage-associated molecular patterns, acting as adjuvants, and expresses Ags that induce a specific antitumor immune response. ICD is studied mainly in the context of regulated cell death pathways, especially
caspase-mediated apoptosis marked by endoplasmic reticulum stress and
calreticulin exposure and, more recently, also in relation to receptor-interacting
protein kinase-driven necroptosis, whereas unregulated cell death like accidental
necrosis is nonimmunogenic. Importantly, the murine
cancer cell lines used in ICD studies often express virally derived
peptides that are recognized by the immune system as
tumor-associated Ags. However, it is unknown how different cell death pathways may affect neoepitope cross-presentation and Ag recognition of
cancer cells. We used a prophylactic
tumor vaccination model and observed that both apoptotic and necroptotic colon
carcinoma CT26 cells efficiently immunized mice against challenge with a
breast cancer cell line that expresses the same immunodominant
tumor Ag, AH1, but only necroptotic CT26 cells would mount an immune response against CT26-specific neoepitopes. By CRISPR/Cas9 genome editing, we knocked out AH1 and saw that only necroptotic CT26 cells were still able to protect mice against
tumor challenge. Hence, in this study, we show that endogenous AH1
tumor Ag expression can mask the strength of immunogenicity induced by different cell death pathways and that upon knockout of AH1, necroptosis was more immunogenic than apoptosis in a prophylactic
tumor vaccination model. This work highlights necroptosis as a possible preferred ICD form over apoptosis in the treatment of
cancer.