Increased expression of the immunosuppressive interleukin-35 in patients with non-small cell lung cancer.

Lisanne Heim, Katerina Kachler, Raphaela Siegmund, Denis I Trufa, Susanne Mittler, Carol-Immanuel Geppert, Juliane Friedrich, Ralf J Rieker, Horia Sirbu, Susetta Finotto

British journal of cancer 2019 Apr

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The immunosuppressive role of the cytokine IL-35 in patients with non-small cell lung cancer (NSCLC) is poorly understood. In this study, we analysed the localisation and regulation of IL-35 in the lung of patients with non-small cell lung cancer (NSCLC) to further elucidate the immune-escape of cancer cells in perioperative course of disease. Interleukin 35 (IL-35) was measured by ELISA in postoperative serum from 7 patients with NSCLC as well as 8 samples from healthy controls. Immunohistochemistry, FACS analysis, real-time PCR, as well as western blot from samples of the control (CTR), peri-tumoural (PT) and the tumoural (TU) region of the lung derived from patients with NSCLC and 10 controls were performed. Here we found elevated levels of IL-35 in the TU region as well as postoperative serum from patients with lung adenocarcinoma. Consistently, we found an increased expression of IL-35+Foxp-3+ cells, which associated with ARG1 mRNA expression and decreased TNFA in the TU region of the lung of patients with NSCLC as compared to their CTR region. Furthermore, in the CTR region of the lung of patients with NSCLC, CD68+ macrophages were induced and correlated with IL-35+ cells. Finally, IL-35 positively correlated with TTF-1+PD-L1+ cells in the TU region of NSCLC patients. Induced IL-35+Foxp3+ cell numbers in the TU region of the lung of patients with NSCLC associated with ARG1 mRNA expression and with TTF-1+PD-L1+ cells. In the tumour-free CTR area, IL-35 correlated with CD68+ macrophages. Thus inhibitors to IL-35 would probably succeed in combination with antibodies against immune checkpoints like PD-L1 and PD-1 currently used against NSCLC because they would inhibit immunosuppressive macrophages and T regulatory cells while promoting T cell-mediated anti-tumoural immune responses in the microenvironment as well as the TU region of NSCLC patients.

Citation

Lisanne Heim, Katerina Kachler, Raphaela Siegmund, Denis I Trufa, Susanne Mittler, Carol-Immanuel Geppert, Juliane Friedrich, Ralf J Rieker, Horia Sirbu, Susetta Finotto. Increased expression of the immunosuppressive interleukin-35 in patients with non-small cell lung cancer. British journal of cancer. 2019 Apr;120(9):903-912