Interferon regulatory factor 3 and NF kappa b are required for expression of immune susceptibility genes in human lung and breast carcinoma cells treated with poly I:C

Immunostimulatory Toll‐like receptor (TLR) and RIG‐I‐like receptor (RLR) agonists, including the viral RNA mimic poly I:C, have been proposed as adjuvant the efficacy of anti‐tumor immunotherapy. In combination with interferon‐gamma, poly I:C may function by direct activation of anti‐tumor M1 macrophages and natural killer (NK) cells. Poly I:C may also drive potent stimulation of dendritic cells, and in turn CD8+ and/or CD4+ T cell responses to enhance recognition of tumor‐associated neoantigens, making it an attractive adjuvant for use in combination with immune checkpoint inhibitors or therapeutic vaccines. However, the potential direct effects of poly I:C on heterogeneic tumor cells in the context of immunotherapeutic strategies are poorly understood. We hypothesized that poly I:C may also directly induce NF‐kappa B activation, and expression of interferon‐stimulated genes (ISG), in tumor cells, thus impacting tumor susceptibility to immune responses. We found that poly I:C and authentic viral RNA induced robust expression of ISG MXA in cultured human lung adenocarcinoma (A549) and metastatic breast carcinoma (ZR‐75‐1) cell lines. In contrast, the type III interferon cytokine IL28A/B was induced in both A549 and ZR‐75‐1 by viral RNA, but only in ZR‐75‐1 by poly I:C, suggesting that tumor cells may differentially retain intact innate immune transcriptional programs. In these tumor cells, poly I:C also induced NKG2D ligands ULBP 1/2/3, MHC I pathway genes TAP, MECL1‐beta, and LMP2, and the immune checkpoint protein PDL2, indicating the poly I:C may directly modulate the susceptibility of tumor cells to NK and CD8+ T cell responses. To understand transcriptional activation driven by poly I:C, we examined the transcription factors IRF3 and NF‐kB. In A549 cells treated with poly I:C, IRF3 translocated to the nucleus, and IRF3 was required for secretion of bioactive cytokines using an interferon‐sensitive VSV‐GFP reporter bioassay. Similarly, poly I:C induced the NF‐kB target gene IL8 in both A549 and ZR‐75‐1, which could be abrogated by NF‐kB inhibitor bay 11‐7082. Taken together, it may be promising to explore the efficacy of poly I:C and other viral RNA mimics to directly adjuvant tumor cell susceptibility to cytotoxic T lymphocytes, adding another dimension to immunotherapy against human tumors. Support or Funding Information NIGMS Alaska INBRE; Portland State University‐University of Alaska Anchorage BUILD EXITO Program; UAA OURS & CAS This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .