title: Primary sterile necrotic cells fail to cross-prime CD8(+) T cells.
abstract: 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.
authors.affiliation: Gastrointestinal Malignancy Section; Medical Oncology Branch; National Cancer Institute; National Institutes of Health; Bethesda, MD USA ; Department of Gastroenterology; Hepatology and Endocrinology; Hannover Medical School; Hanover, Germany.
authors.forename: Jaba
authors.initials: J
authors.lastname: Gamrekelashvili
authors.forename: Lars A
authors.initials: LA
authors.lastname: Ormandy
authors.forename: Markus M
authors.initials: MM
authors.lastname: Heimesaat
authors.forename: Carsten J
authors.initials: CJ
authors.lastname: Kirschning
authors.forename: Michael P
authors.initials: MP
authors.lastname: Manns
authors.forename: Firouzeh
authors.initials: F
authors.lastname: Korangy
authors.forename: Tim F
authors.initials: TF
authors.lastname: Greten