Pancreatic cancer is characterized by a microenvironment suppressing immune responses. RIG-I-like helicases (RLH) are immunoreceptors for
viral RNA that induce an
antiviral response program via the production of
type I interferons (IFN) and apoptosis in susceptible cells. We recently identified RLH as therapeutic targets of
pancreatic cancer for counteracting immunosuppressive mechanisms and apoptosis induction. Here, we investigated immunogenic consequences of RLH-induced
tumor cell death. Treatment of murine
pancreatic cancer cell lines with RLH
ligands induced production of type I IFN and proinflammatory
cytokines. In addition,
tumor cells died via intrinsic apoptosis and displayed features of immunogenic cell death, such as release of
HMGB1 and translocation of
calreticulin to the outer cell membrane. RLH-activated
tumor cells led to activation of dendritic cells (DCs), which was mediated by
tumor-derived type I IFN, whereas TLR, RAGE or
inflammasome signaling was dispensable. Importantly, CD8α(+) DCs effectively engulfed apoptotic
tumor material and cross-presented
tumor-associated
antigen to naive CD8(+) T cells. In comparison,
tumor cell death mediated by
oxaliplatin,
staurosporine or mechanical disruption failed to induce DC activation and antigen presentation.
Tumor cells treated with sublethal doses of RLH
ligands upregulated Fas and MHC-I expression and were effectively sensitized towards Fas-mediated apoptosis and cytotoxic T lymphocyte (CTL)-mediated lysis. Vaccination of mice with RLH-activated
tumor cells induced protective antitumor immunity in vivo. In addition, MDA5-based
immunotherapy led to effective
tumor control of established pancreatic
tumors. In summary, RLH
ligands induce a highly immunogenic form of
tumor cell death linking innate and adaptive immunity.