Insufficient CD100 shedding contributes to suppression of CD8+ T-cell activity in non-small cell lung cancer.

CD100 is an immune semaphorin constitutively expressed on T-cells. Matrix metalloproteinase (MMP) is an important mediator of membrane-bound CD100 (mCD100) cleavage to generate soluble CD100 (sCD100), which has immunoregulatory activity in immune cell responses. The aim of the study was to investigate the level and role of sCD100 and mCD100 in modulating CD8+ T-cell function in non-small cell lung cancer (NSCLC). sCD100 and MMP-14 levels in the serum and bronchoalveolar lavage fluid (BALF), and mCD100 expression on peripheral and lung-resident CD8+ T-cells were analysed in NSCLC patients. The ability to induce sCD100 and the effect of MMP-14 on mCD100 shedding for the regulation of non-cytolytic and cytolytic functions of CD8+ T-cells were also analysed in direct and indirect contact co-culture systems. NSCLC patients had lower serum sCD100 and higher mCD100 levels on CD8+ T-cells compared with healthy controls. BALF from the tumour site also had decreased sCD100 and increased mCD100 on CD8+ T-cells compared with the non-tumour site. Recombinant CD100 stimulation enhanced non-cytolytic and cytolytic functions of CD8+ T-cells from NSCLC patients, whereas blockade of CD100 receptor CD72 attenuated CD8+ T-cell activity. NSCLC patients had lower MMP-14 in the serum and in BALF from the tumour site. Recombinant MMP-14 mediated mCD100 shedding from CD8+ T-cell membrane, and led to promotion of CD8+ T-cell response in NSCLC patients. Overall, decreased MMP-14 resulted in insufficient CD100 shedding, leading to suppression of peripheral and lung-resident CD8+ T-cell activity in NSCLC.

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

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.

[Correlation between Gan Depression Qi Stagnation Syndrome and Thyroid Stimulating Hormone Level in Adolescent Polycystic Ovary Syndrome Patients].

Objective To observe the distribution features of Gan depression qi stagnation syndrome (GDQSS) , and to analyze the correlation between GDQSS scores and thyroid stimulating hormone (TSH) level in adolescent polycystic ovary syndrome (PCOS) patients. Methods Disease location and disease nature were syndrome identified in PCOS outpatients confirmed at Department of Gynecology, Ningbo Municipal Hospital of TCM. Totally 110 patients in line with GDQSS were graded by GDQSS score from low to high. GDQSS score ranging 70 -100 belonged to grade I (mild) ; 101 -150 to grade II (moderate) ; >150 to grade III (severe). The correlation between the severity of GDQSS and TSH level was an- alyzed using Pearson and Partial correlation analyses. Results Levels of TSH, testosterone (T) , pro- lactin (PRL) were the lowest in grade I GDQSS patients, and they were the highest in grade lIl GDQSS patients (P <0. 01). Pearson correlation analysis showed that GDQSS score was positively correlated with TSH level (r =0. 676, P <0. 01). They were still positively correlated by using Partial correlation after controlling body mass index (BMI) , waist hip ratio (WHR) , homeostasis model of assessment-insulin resistance (HOMR-IR) factors (r =0. 663, P <0. 01). Conclusion Adolescent PCOS patients with obvi- ous GDQSS symptoms might be associated with increased TSH level.