Primary sterile necrotic cells fail to cross-prime CD8+ T cells

• Published in: Oncoimmunology 2012-10, Vol.1 (7), p.1017-1026
• Main Authors: Gamrekelashvili, Jaba, Ormandy, Lars A., Heimesaat, Markus M., Kirschning, Carsten J., Manns, Michael P., Korangy, Firouzeh, Greten, Tim F.
• Format: Article
• Language: English
• Subjects: Binding; Biology; Bioscience; Calcium; Cancer; cancer vaccine; CD8; Cell; cross-priming; Cycle; death; Landes; Organogenesis; Proteins; Research Paper; sterile necrosis; T cells; tumor cells
• ISSN: 2162-4011; 2162-402X; 2162-402X
• DOI: 10.4161/onci.21098

Necrotic cells are known to activate the innate immune system and trigger inflammation by releasing damage associated molecular patterns (DAMPs). However, 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), remains poorly understood. Here, 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.