Kirsten rat sarcoma viral oncogene (K-ras) is a well-documented, frequently mutated gene in lung cancer. Since K-ras regulates numerous signaling pathways related to cell survival and proliferation, mutations in this gene are powerful drivers of tumorigenesis and confer prodigious survival advantages to developing tumors. These malignant cells dramatically alter their local tissue environment and in the process recruit a powerful ally: inflammation. Inflammation in the context of the tumor microenvironment can be described as either antitumor or protumor (i.e., aiding or restricting tumor progression, respectively). Many current treatments, like immune checkpoint blockade, seek to augment antitumor inflammation by alleviating inhibitory signaling in cytotoxic T cells; however, a burgeoning area of research is now focusing on ways to modulate and mitigate protumor inflammation. Here, we summarize the interplay of tumor-promoting inflammation and K-ras mutant lung cancer pathogenesis by exploring the cytokines, signaling pathways, and immune cells that mediate this process.

MJT and BFD may work with their institution to file a patent based on the identification of a pharmacologic compound to inhibit stimulated mucin secretion as a therapeutic strategy to ameliorate airway mucus obstruction. BFD is a member of a scientific advisory board for Arrowhead Pharmaceuticals, which is using RNA interference to treat diseases affecting multiple organs, including mucus obstructive airway diseases, and his laboratory has received funding from Arrowhead Pharmaceuticals.

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K-ras mutant lung adenocarcinoma (LUAD) is the most common type of lung cancer, displays abysmal prognosis, and is tightly linked to tumor-promoting inflammation, which is increasingly recognized as a target for therapeutic intervention. We have recently shown a gender-specific role for epithelial Stat3 signaling in the pathogenesis of K-ras mutant LUAD. Absence of epithelial Stat3 in male K-ras mutant mice (LR/Stat3Δ/Δ mice) promoted tumorigenesis and induced an NF-κB driven pro-tumor immune response while reducing tumorigenesis and enhancing anti-tumor immunity in female counterparts. In the present study, we manipulated estrogen and NF-κB signaling to study the mechanisms underlying this intriguing gender-disparity. In LR/Stat3Δ/Δ females, estrogen deprivation by bilateral oophorectomy resulted in higher tumor burden, an induction of NF-κB driven immuno-suppressive response, and reduced anti-tumor cytotoxicity, while estrogen replacement reversed these changes. On the other hand, exogenous estrogen in males successfully inhibited tumorigenesis, attenuated NF-κB driven immunosuppression, and boosted anti-tumor immunity. Mechanistically, genetic targeting of epithelial NF-κB activity resulted in reduced tumorigenesis and enhanced the anti-tumor immune response in LR/Stat3Δ/Δ males but not females. Our data suggest that estrogen exerts a context-specific anti-tumor effect through inhibiting NF-κB driven tumor-promoting inflammation and provide insights into developing novel personalized therapeutic strategies for K-ras mutant LUAD.

IntroductionToll-like receptors (TLRs) are an extensive group of proteins involved in host defense processes that express themselves upon the increased production of endogenous damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) due to the constant contact that airway epithelium may have with pathogenic foreign antigens. We have previously shown that COPD-like airway inflammation induced by exposure to an aerosolized lysate of nontypeable Haemophilus influenzae (NTHi) promotes tumorigenesis in a K-ras mutant mouse model of lung cancer, CCSPCre/LSL-K-rasG12D (CC-LR) mouse.MethodsIn the present study, we have dissected the role of TLRs in this process by knocking out TLR2, 4, and 9 and analyzing how these deletions affect the promoting effect of COPD-like airway inflammation on K-ras-driven lung adenocarcinoma.ResultsWe found that knockout of TLR 2, 4, or 9 results in a lower tumor burden, reduced angiogenesis, and tumor cell proliferation, accompanied by increased tumor cell apoptosis and reprogramming of the tumor microenvironment to one that is antitumorigenic. Additionally, knocking out of downstream signaling pathways, MyD88/NF-κB in the airway epithelial cells further recapitulated this initial finding.DiscussionOur study expands the current knowledge of the roles that TLR signaling plays in lung cancer, which we hope, can pave the way for more reliable and efficacious prevention and treatment modalities for lung cancer.