Interleukin-35 Suppresses the Antitumor Activity of T Cells in Patients with Non-Small Cell Lung Cancer

Abstract

Background/Aims: Interleukin (IL)-35 has immunosuppressive functions in autoimmune diseases, infectious diseases, and certain cancers. However, few studies have focused on its immunoregulatory activity in non-small cell lung cancer (NSCLC). Thus, we investigated the role of IL-35 in the pathogenesis of this disease. Methods: A total of 66 NSCLC patients and 21 healthy individuals were enrolled. IL-35 expression in peripheral blood and bronchoalveolar lavage fluid (BALF) was measured. The modulatory functions of IL-35 on purified CD4⁺ and CD8⁺ T cells from NSCLC patients were investigated in direct and indirect coculture systems with NSCLC cell lines. Results: IL-35 expression was significantly increased in BALF from the tumor site, but not in the peripheral blood of NSCLC patients. IL-35 did not affect the bioactivity including proliferation, cytokine production, cell cycle, and cellular invasion of NSCLC cells. It suppressed responses from type 1 T helper (Th1) and Th17 cells but elevated the regulatory T cell response in cultured CD4⁺ T cells from NSCLC patients, and reduced cytokine-mediated CD4⁺ T cells cytotoxicity to NSCLC cells. Moreover, IL-35 also inhibited cytotoxic gene expression in CD8⁺ T cells from NSCLC, reducing their cytolytic and noncytolytic functions. Conclusion: The results of this study suggest that IL-35 contributes to the dysfunction/exhaustion of T cells and limited antitumor immune responses in NSCLC.

Predictive biomarkers and mechanisms underlying resistance to PD1/PD-L1 blockade cancer immunotherapy

“…Some interleukins have a negative regulatory role in T cell function. IL-35 inhibits the expression of cytotoxic genes in CD8 + T cells and reduces cytolytic and noncytolytic functions [106]. Recent studies have shown that the Notch signaling pathway may inhibit FASL and perforin, resulting in decreased activity and dysfunction of CD8 + T cells ( Fig.…”

The role of B lymphocytes in the immuno-biology of non-small-cell lung cancer

“…Numerous studies have phenotypically characterised various Breg subsets in health and disease, this is displayed in Table 2 [58,59,[61][62][63][64][65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80]. The findings from these studies of human Bregs in cancer underscores the ability of different Breg subsets to mediate immunosuppression in support of CD39 + CD73+ Adenosine Healthy human donor peripheral blood Saze et al [78] (iBreg subtype) TGF-P, IDO Healthy human donor peripheral blood Nouel et al [80] CD19 + TIM-1+ IL-10 HIV-1 Infection Liu et al [79] tumour growth through a variety of mechanisms; suppressive cytokine production (IL-10, TGF-β, IL-35), suppression of T cells and NK cells and the expansion of suppressive Tregs and myeloid-derived suppressor cells [30], expression of inhibitory ligands such as PD-L1 to dampen anti-tumour immunity [81] and STAT3 mediated promotion of angiogenesis and Treg augmentation [22,68,82].…”

CD19+ CD24hi CD38hi Regulatory B Cells and Memory B Cells in Periodontitis: Association with Pro-Inflammatory and Anti-Inflammatory Cytokines

“…IL35 may also play a vital role in the immune suppression function of Breg cells. Moreover, a recent study has reported that IL-35 contributes to the dysfunction/exhaustion of T cells and limited antitumor immune responses in Non-Small Cell Lung Cancer [ 33 ].…”