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

Abstract

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

IL-12 Family Cytokines in Cancer and Immunotherapy

“…This information may lead to the development of new immunotherapeutic agents for the treatment of cancer patients, and it can be used as a potential biomarker for disease progression. As an example, elevated levels of IL-35 have been associated with poor prognosis in many solid cancer types [ 183 , 184 , 185 , 186 ].…”

“…Similarly, the loss of B cell-specific IL-35 expression or antibody-based IL-35 blockade synergized with anti-PD1 treatment in a CD8 + T cell-dependent manner to inhibit pancreatic cancer growth in preclinical models [ 169 ]. A similar approach of combining IL-35 blockade with the immune checkpoint inhibition of PD1 or PD-L1 was effective in NSCLC [ 185 ]. In this case, the neutralization of IL-35 hindered immunosuppressive macrophages and Treg cells while enhancing anti-tumor immunity.…”

Interleukin-35 promotes progression of prostate cancer and inhibits anti-tumour immunity

“…Treg cells have a vital effect on inhibiting antitumour immunity by hindering the protective immune surveillance of the tumour, inducing immune escape, and blocking the effective antitumour immune response of the tumour-bearing host [ 4 ]. In the context of tumours, a large number of Treg cells were often detected, which inhibited or reduced these effector lymphocytes, such as CD4+ T cells and CD8+ cytotoxicity T lymphocytes (CTL), achieving antitumour immune responses [ 43 – 45 ]. CD4+ T cells were reported to be helper T cells, which are capable of promoting effective antitumour immune responses.…”

The Role of IL-35 in the Pathophysiological Processes of Liver Disease

“…Elevated expression level of IL-35 in serum in HCC patients might act as an independent prognostic indicator ( Yang et al, 2019b ). Furthermore, circulating IL-35 expression level might suggest the dysfunctional immune system in anti-tumor response, showing the activation of Tregs and the apoptosis of CD8+ T cell ( Heim et al, 2019 ). Moreover, IL-35 expression level was positively correlated with intrahepatic cholangiocarcinoma (ICC) aggressiveness, and served as an independent prognostic factor ( Xing and Tian, 2020 ).…”