SIRT6 regulates the cigarette smoke-induced signalling in rheumatoid arthritis synovial fibroblasts

Cigarette smoking is a recognized environmental risk factor for the development and progression of rheumatoid arthritis (RA). RA synovial fibroblasts (RASF) actively contribute to inflammation and joint destruction in this chronic inflammatory autoimmune disease. In the current study, we investigated the influence of cigarette smoke on the inflammatory and matrix-destructive properties of RASF. Furthermore, the functional role of Sirtuin 6 (SIRT6) in the regulation of the signalling induced by cigarette smoke or by tumor necrosis factor alpha (TNFα) was elucidated. We demonstrated that stimulation with cigarette smoke extract (CSE) enhances the pro-inflammatory and matrix-destructive potential of RASF by inducing the production of pro-inflammatory cytokine interleukin 8 (IL8) and the matrix-destructive enzyme matrix metalloproteinase 1 (MMP1), but not of IL6 and MMP3. Moreover, we could show that the expression of MMP1 is specifically regulated by SIRT6. Treatment of RASF with CSE or TNFα increased the levels of SIRT6. The expression of SIRT6 was also enhanced in vivo in synovial tissues of RA smokers and in joints of mice exposed to cigarette smoke. Silencing of SIRT6 specifically increased basal as well as CSE- and TNFα-induced production of MMP1, demonstrating that SIRT6 plays an important role in restricting MMP1 expression. In conclusion, the upregulation of SIRT6 in RASF under CSE or TNFα stimulation functions as a counterregulatory mechanism attenuating the production of the matrix-destructive enzyme MMP1. This is the first study revealing the protective function of SIRT6 in the cigarette smoke-induced signalling. KEY MESSAGES: Cigarette smoke induces pro-inflammatory and matrix-destructive responses in RASF. Cigarette smoke enhances the expression of SIRT6 in vitro and in vivo. TNFα increases the levels of SIRT6. SIRT6 diminishes MMP1 production under cigarette smoke extract and TNFα stimulation

Association of Checkpoint Inhibitor–Induced Toxic Effects With Shared Cancer and Tissue Antigens in Non–Small Cell Lung Cancer

Importance: Immunotherapy with checkpoint inhibitors targeting the PD-1 (programmed cell death 1) axis has brought notable progress in patients with non–small cell lung cancer (NSCLC) and other cancers. However, autoimmune toxic effects are frequent and poorly understood, making it important to understand the pathophysiologic processes of autoimmune adverse effects induced by checkpoint inhibitor therapy. Objective: To gain mechanistic insight into autoimmune skin toxic effects induced by anti–PD-1 treatment in patients with non–small cell lung cancer. Design, Setting, and Participants: This prospective cohort study was conducted from July 1, 2016, to December 31, 2018. Patients (n = 73) with non–small cell lung cancer who received anti–PD-1 therapy (nivolumab or pembrolizumab) were recruited from 4 different centers in Switzerland (Kantonsspital St Gallen, Spital Grabs, Spital Wil, and Spital Flawil). Peripheral blood mononuclear cells, tumor biopsy specimens and biopsies from sites of autoimmune skin toxic effects were collected over a 2-year period, with patient follow-up after 1 year. Main Outcomes and Measures: Response to treatment, overall survival, progression-free survival, and development of autoimmune toxic effects (based on standard laboratory values and clinical examinations). Results: Of the cohort of 73 patients with NSCLC (mean [SD] age, 68.1 [8.9] years; 44 [60%] men), 25 (34.2% [95% CI, 24.4%-45.7%]) developed autoimmune skin toxic effects, which were more frequent in patients with complete remission or partial remission (68.2% [95% CI, 47.3%-83.6%]) than those with progressive or stable disease (19.6% [95% CI, 11.0%-32.5%]) (χ2 = 14.02, P < .001). Nine T-cell antigens shared between tumor tissue and skin were identified. These antigens were able to stimulate CD8+ and CD4+ T cells in vitro. Several of the antigen-specific T cells found in blood samples were also present in autoimmune skin lesions and lung tumors of patients who responded to anti–PD-1 therapy. Conclusions and Relevance: These findings highlight a potential mechanism of checkpoint inhibitor–mediated autoimmune toxic effects and describe the association between toxic effects and response to therapy; such an understanding will help in controlling adverse effects, deciphering new cancer antigens, and further improving immunotherapy