IL6 Blockade Reprograms the Lung Tumor Microenvironment to Limit the Development and Progression of K-ras–Mutant Lung Cancer

Abstract

Activating mutations of K-ras are the most common oncogenic alterations found in lung cancer. Unfortunately, attempts to target K-ras mutant lung tumors have thus far failed, clearly indicating the need for new approaches in patients with this molecular profile. We have previously shown NF-κB activation, release of IL-6, and activation of its responsive transcription factor STAT3 in K-ras mutant lung tumors, which was further amplified by the tumor enhancing effect of chronic obstructive pulmonary disease (COPD)-type airway inflammation. These findings suggest an essential role for this inflammatory pathway in K-ras mutant lung tumorigenesis and its enhancement by COPD. Therefore, here we blocked IL-6 using a monoclonal anti-IL-6 antibody in a K-ras mutant mouse model of lung cancer in the absence or presence of COPD-type airway inflammation. IL-6 blockade significantly inhibited lung cancer promotion, tumor cell intrinsic STAT3 activation, tumor cell proliferation, and angiogenesis markers. Moreover, IL-6 inhibition reduced expression of pro-tumor type 2 molecules (Arginase 1, Fizz 1, Mgl, and IDO), number of M2 type macrophages and G-MDSCs, and pro-tumor T-regulatory/T helper 17 cell responses. This was accompanied by increased expression of anti-tumor type 1 molecule (Nos2), and anti-tumor T helper 1/CD8 T cell responses. Our study demonstrates that IL-6 blockade not only has direct intrinsic inhibitory effect on tumor cells, but also re-educates the lung microenvironment toward an anti-tumor phenotype by altering the relative proportion between pro-tumor and anti-tumor immune cells. This information introduces IL-6 as a potential druggable target for prevention and treatment of K-ras mutant lung tumors.

Autocrine activin A signalling in ovarian cancer cells regulates secretion of interleukin 6, autophagy, and cachexia

“…We have previously found that the CM from TOV21G cells accelerates autophagy in other cells and have largely attributed this effect to their secretion of IL‐6 . TOV21G cells are known to have an activating KRAS mutation, and this has been shown to be important for IL‐6 production, especially in murine lung cancer models . We therefore wanted to establish whether activated KRAS was a major contributor to the IL‐6 production in our model system.…”

Clinical Significance of miR-210 and its Prospective Signaling Pathways in Non-Small Cell Lung Cancer: Evidence from Gene Expression Omnibus and the Cancer Genome Atlas Data Mining with 2763 Samples and Validation via Real-Time Quantitative PCR

“…All of these findings suggest that IL-6 might be a crucial potential therapeutic target in lung cancer. Actually, Caetano et al found that anti-IL-6 treatment could be an alternative therapeutic strategy in lung cancer [76]. Interestingly the reaction of patients with NSCLC to analgesics could be predicted by detecting a gene polymorphism of IL-6, which has shown significant value in improving the quality of life and prognosis of such patients [77].…”

Role of CPS1 in Cell Growth, Metabolism, and Prognosis in LKB1-Inactivated Lung Adenocarcinoma

“…Recent studies have reported activation of the JAK/STAT pathway in sex-determining region Y box 2 (SOX2)-driven, LKB1-deficient mouse model of squamous cell lung cancer (47) and increase of IL-6 production and subsequent activation of STAT3 in LKB1-deficient mouse model of LADC (48,49). As IL-6/JAK/STAT signaling axis plays important roles in cell proliferation, survival, invasion, chemoresistance, and immunosuppression, (48,(50)(51)(52)(53), targeting CPS1 might alter tumor microenvironment and improve efficiency of immunotherapy.…”