Analysis of tumor cell death on antigen-specific immune responses

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The way in which tumor cells die is proposed to have a substantial impact on the generation of adaptive immune responses. In our previous studies we have been able to demonstrate that induction of apoptosis versus necrosis in subcutaneously growing tumors has profoundly different effects on tumor specific CD8+ T cells. While apoptotic tumor cell death promote anti-tumor immune responses necrotic tumor cell death impair these responses. In 2012 we have been able to study how necrotic cells influence the induction of antigen-specific CD8+ T cell-mediated adaptive immune responses under sterile conditions, in the absence of pathogen associated molecular patterns (PAMPs). We examined antigen-specific CD8+ T cell responses to primary sterile necrotic tumor cells both in vitro and in vivo. We found that primary necrotic cells alone fail to generate CD8+ T cell-dependent immune responses toward cell-associated antigens. We show that necrotic cells trigger CD8+ T-cell immunity only in the presence of PAMPs or analogs, such as p(dI-dC) and/or unmethylated CpG DNA. The electroporation of tumor cells with these PAMPs prior to necrosis induction triggered antigen-specific CD8+ T-cell responses through a TLR9/MyD88-dependent pathway. In addition, we found that necrotic cells contain factors that can block the cross-priming of CD8+ T cells even under non-sterile conditions and can serve as a possible mechanism of immunosuppression. These results suggest that antigen-specific CD8+ T-cell responses to primary necrotic tumor cells can be induced in the presence of PAMPs and thus have a substantial impact on the development of antitumor vaccination strategies.