RIG-I-like helicases induce immunogenic cell death of pancreatic cancer cells and sensitize tumors toward killing by CD8+ T cells

Abstract

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, CD8aþ DCs effectively engulfed apoptotic tumor material and cross-presented tumorassociated antigen to naive CD8 þ 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.

Effects of retinoic acid-inducible gene-I-like receptors activations and ionizing radiation cotreatment on cytotoxicity against human non-small cell lung cancer in�vitro

“…For example, some researcher focused on the recognition of 5'-triphosphate single-stranded RNAs by RIG-I, and designed the 5'-triphosphate-siRNA (8,18,19). sensitized pancreatic cancer cells towards Fas-mediated cell killing (20). In the present study, we focused on the ionizing radiation to improve RLR agonist-induced cytotoxicity, and showed that cotreatment with RLR agonist and ionizing radiation effectively induced the cytotoxicity against cancer cells for the first time.…”

Immunological metagene signatures derived from immunogenic cancer cell death associate with improved survival of patients with lung, breast or ovarian malignancies: A large-scale meta-analysis

“…A limited number of retrospective studies carried out in human cancer patients to ascertain whether ICD-associated parameters can be used as prognostic biomarkers, have yielded contradictory results. [28][29][30][31][32][33][34][35] Possible reasons for this could be restriction to a few ICDderived biomarkers (mainly calreticulin, HMGB1 or CD73), the limited number of patients and variations related to cancer-types.…”

Paradoxical Role of HMGB1 in Pancreatic Cancer: Tumor Suppressor or Tumor Promoter?

“…Local treatment of potentially resectable pancreatic cancers with RLH ligands that would carry a highly immunogenic form of cell death before surgery may facilitate the induction of a T-cellmediated antitumor immune response with the potential to control outgrowth of residual tumor cells (7).…”

“…The pathway involves type I interferon (IFN) (7,20) with a double action; it alerts the immune system to danger leading to activation of dendritic and effector cells, while it stops inhibition of immunosuppressive cells, such as regulatory T cells (20). Local treatment of potentially resectable pancreatic cancers with RLH ligands that would carry a highly immunogenic form of cell death before surgery may facilitate the induction of a T-cellmediated antitumor immune response with the potential to control outgrowth of residual tumor cells (7).…”

“…Through a signaling pathway involving the receptor for advanced glycation end products (RAGE), HMGB1 has been associated with tumor progression due to its elevated expression in certain cancer types, especially pancreatic cancer (3). Likewise, HMGB1 has been correlated to invasion and metastasis (4), resistance to chemotherapy agents (5,6) and autophagy and immunogenic cell death (7).…”