Lack or loss of tumor antigenicity represents one of the key mechanisms of immune escape and resistance to T cell–based immunotherapies. Evidence suggests that activation of stimulator of interferon genes (STING) signaling in tumor cells can augment their antigenicity by triggering a type I IFN-mediated sequence of autocrine and paracrine events. Although suppression of this pathway in melanoma and other tumor types has been consistently reported, the mechanistic basis remains unclear. In this study, we asked whether this suppression is, in part, epigenetically regulated and whether it is indeed a driver of melanoma resistance to T cell–based immunotherapies. Using genome-wide DNA methylation profiling, we show that promoter hypermethylation of cGAS and STING genes mediates their coordinated transcriptional silencing and contributes to the widespread impairment of the STING signaling function in clinically-relevant human melanomas and melanoma cell lines. This suppression is reversible through pharmacologic inhibition of DNA methylation, which can reinstate functional STING signaling in at least half of the examined cell lines. Using a series of T cell recognition assays with HLA-matched human melanoma tumor-infiltrating lymphocytes (TIL), we further show that demethylation-mediated restoration of STING signaling in STING-defective melanoma cell lines can improve their antigenicity through the up-regulation of MHC class I molecules and thereby enhance their recognition and killing by cytotoxic T cells. These findings not only elucidate the contribution of epigenetic processes and specifically DNA methylation in melanoma-intrinsic STING signaling impairment but also highlight their functional significance in mediating tumor-immune evasion and resistance to T cell–based immunotherapies.
Background The use of laparoscopic surgery has become widespread, and many surgeons are striving to acquire the necessary techniques for it. The Endoscopic Surgical Skill Qualification System (ESSQS), established by the Japan Society for Endoscopic Surgery, serves to maintain and improve the quality of laparoscopic surgery in Japan. In this study, we aimed to determine whether ESSQS certification is useful in maintaining and improving the quality of surgical techniques and in standardization of laparoscopic surgery in Japan. Methods This retrospective study used data from the Institute for Integrated Medical Sciences, Tokyo Women’s Medical University , Japan. From January 2016 to October 2017, 241 patients with colorectal cancer underwent laparoscopic surgery. Of them, 220 patients were selected and divided into two groups on the basis of surgery performed by an ESSQS-qualified surgeon (QS group) ( n = 170) and a non-ESSQS-QS (NQS) ( n = 50). We compared the short-term results in the two groups and examined those before and after propensity score matching (PSM). Results Mean operation time was longer in the NQS group than in the QS group. Furthermore, mean blood loss was significantly less in the QS group. These were similar before and after PSM. The rate of conversion to open surgery was significantly higher in the NQS group before PSM. However, the rate of postoperative complications was not different between the two groups. Conclusions A laparoscopic procedure performed by ESSQS-QS often leads to good short-term outcomes. Thus, the ESSQS system works and is potentially useful in maintaining and improving the quality of surgical techniques and in standardization of laparoscopic surgery in Japan.
Tertiary lymphoid structures (TLS) are ectopically formed aggregates of organized lymphocytes and antigen-presenting cells that occur in solid tissues as part of a chronic inflammation response. Sharing structural and functional characteristics with conventional secondary lymphoid organs (SLO) including discrete T cell zones, B cell zones, marginal zones with antigen presenting cells, reticular stromal networks, and high endothelial venues (HEV), TLS are prominent centers of antigen presentation and adaptive immune activation within the periphery. TLS share many signaling axes and leukocyte recruitment schemes with SLO regarding their formation and function. In cancer, their presence confers positive prognostic value across a wide spectrum of indications, spurring interest in their artificial induction as either a new form of immunotherapy, or as a means to augment other cell or immunotherapies. Here, we review approaches for inducible (iTLS) that utilize chemokines, inflammatory factors, or cellular analogues vital to TLS formation and that often mirror conventional SLO organogenesis. This review also addresses biomaterials that have been or might be suitable for iTLS, and discusses remaining challenges facing iTLS manufacturing approaches for clinical translation.
BackgroundGastric lipomatosis is characterized by multiple gastric lipomas or a diffuse gastric infiltration of the submucosal or subserosal layer by the adipose tissue; diffuse-type gastric lipomatosis is an extremely rare condition. Here, we present the case of a patient with gastric lipomatosis treated by total gastrectomy.Case presentationA 54-year-old man diagnosed with gastric submucosal tumor in 2008 was referred to our hospital for further examination and treatment in September 2016. Upper gastrointestinal endoscopy revealed a submucosal tumor with an associated ulcer on the anterior wall of the lower body of the stomach. A compressing mass was observed on the anterior wall of the greater curvature and the posterior wall of the stomach. Following a biopsy of the submucosal tumor and ulcer, lipoma without malignancy was diagnosed by microscopy. A giant gastric lipoma was suspected because endoscopic ultrasound revealed a high-echoic lesion on the antral wall that extended to the stomach. Therefore, total gastrectomy was performed, and gastric lipomatosis was confirmed by a histological examination of the resected specimen.ConclusionsSurgical treatment is a highly effective treatment for symptomatic gastric lipomatosis with extensive involvement or multiple lipomas and can be used for patient diagnosis.
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