Here we describe increased expression of IL6R in the tumoural region of lung tissue from patients affected by lung adenocarcinoma as compared to squamous cell lung carcinoma. Moreover, here we found increased IL6R in the tumour free part of the lung. By using a murine model of lung adenocarcinoma, we discovered that few lung tumour cells expressed IL-6R and CD4+CD25+Foxp-3+ T regulatory cells down-regulated IL-6R in the tumour bearing lungs. Downstream of IL-6R, the Th17 lineage-specification factors: Signal transducer and activator of transcription 3 (STAT3), Basic leucine zipper transcription factor, BATF and a protein encoded by the RORC in human (RAR-related orphan receptor C) (RORγT), were also found induced in the tumoural region of lung tissue from patients affected by lung adenocarcinoma as compared to those carrying squamous cell carcinoma. Moreover, pSTAT3 protein was found phosphorylated and auto-phosphorylated in the tumoural region of patients with adeno cell carcinoma of the lung as compared to the tumoural region of patients with squamous cell carcinoma of the lung. Intranasal application of anti-IL-6R antibodies in a murine model of lung adenocarcinoma, induced T regulatory cell markers such as Foxp3, Ctla4, Icos, Il10, Il21, Folr4 and Lag3 and inhibited Rorc in lung adenocarcinoma.

Non-small cell lung cancer (NSCLC) is associated with high mortality worldwide underlining the need for novel therapeutic approaches. Signal transducer and activator of transcription 3 (STAT3) is activated via pro-inflammatory cytokines and growth factors (e.g. IL-6, EGF, VEGF) and may promote tumorigenesis by regulating cellular senescence, proliferation and apoptosis. We recently found an upregulation of the IL-6R expression in the tumoral region of patients with lung adenocarcinoma (ADC) as compared to the tumoral region of patients with squamous cell lung carcinoma (SCC). Consistently, increased levels of pSTAT3 were observed in the tumoral region of ADC as compared to SCC patients. Moreover, stimulation of A549 lung adenocarcinoma cells with IL-6 activates pSTAT3 and promotes cell proliferation. STAT3 is also important for the differentiation of both Foxp3+ T regulatory cells which suppress the anti-tumor immune response and RORγt+ T helper 17 cells, a T cell subtype expanded in lung adenocarcinoma. Indeed, ablation of STAT3 in hematopoietic cells triggers an intrinsic immune-surveillance system that inhibits tumor growth and metastasis. However, the role of STAT3 in tumor-infiltrating lymphocytes (TIL) in NSCLC is largely unknown. We therefore will investigate the functional effects of STAT3 inactivation in T cells in a murine model of lung adenocarcinoma by using mice with conditional inactivation of STAT3 (STAT3fl/flCD4Cre). To detect STAT3-regulated genes we will isolate TIL of tumor-bearing STAT3 conditional knockout mice and control littermates. These studies will provide new insights into the functional role of STAT3 in NSCLC and may lead to novel immunotherapeutic approaches for this disease.