TIGIT/CD155 axis mediates resistance to immunotherapy in patients with melanoma with the inflamed tumor microenvironment

Background Patients with cancer benefit from treatment with immune checkpoint inhibitors (ICIs), and those with an inflamed tumor microenvironment (TME) and/or high tumor mutation burden (TMB), particularly, tend to respond to ICIs; however, some patients fail, whereas others acquire resistance after initial response despite the inflamed TME and/or high TMB. We assessed the detailed biological mechanisms of resistance to ICIs such as programmed death 1 and/or cytotoxic T-lymphocyte-associated protein 4 blockade therapies using clinical samples. Methods We established four pairs of autologous tumor cell lines and tumor-infiltrating lymphocytes (TILs) from patients with melanoma treated with ICIs. These tumor cell lines and TILs were subjected to comprehensive analyses and in vitro functional assays. We assessed tumor volume and TILs in vivo mouse models to validate identified mechanism. Furthermore, we analyzed additional clinical samples from another large melanoma cohort. Results Two patients were super-responders, and the others acquired resistance: the first patient had a non-inflamed TME and acquired resistance due to the loss of the beta-2 microglobulin gene, and the other acquired resistance despite having inflamed TME and extremely high TMB which are reportedly predictive biomarkers. Tumor cell line and paired TIL analyses showed high CD155, TIGIT ligand, and TIGIT expression in the tumor cell line and tumor-infiltrating T cells, respectively. TIGIT blockade or CD155-deletion activated T cells in a functional assay using an autologous cell line and paired TILs from this patient. CD155 expression increased in surviving tumor cells after coculturing with TILs from a responder, which suppressed TIGIT+ T-cell activation. Consistently, TIGIT blockade or CD155-deletion could aid in overcoming resistance to ICIs in vivo mouse models. In clinical samples, CD155 was related to resistance to ICIs in patients with melanoma with an inflamed TME, including both primary and acquired resistance. Conclusions The TIGIT/CD155 axis mediates resistance to ICIs in patients with melanoma with an inflamed TME, promoting the development of TIGIT blockade therapies in such patients with cancer

Association between clinical decision for patients with COVID-19 and post-traumatic stress symptoms among healthcare professionals during the COVID-19 pandemic

Objectives: This study aimed to investigate the relationship between clinical decision for the novel coronavirus disease 2019 (COVID-19) patients and post-traumatic stress symptoms (PTSS) among healthcare professionals during the COVID-19 pandemic. Methods: Japanese healthcare professionals were recruited. The survey was conducted from May 21 to June 18, 2021. PTSS was assessed by the Impact of Event Scale-Revised. Items about the experience of clinical decision for COVID-19 patients and other independent variables were originally developed from previous studies. Univariate and multiple linear regression analyses were used to examine the association of independent variables and PTSS. Results: 515 (3.9%) healthcare professionals completed all questions. Among them, 172 (33.4%) had experienced clinical decision for COVID-19 patients. Multiple linear regression analysis showed that clinical decision for COVID-19 patients (B=3.32, 95% CI 1.41–5.24; p<0.01), as well as fear of getting a COVID-19 infection (B=2.15, 95% CI 0.32–3.98; p=0.02), were significantly associated with PTSS in the adjusted model. Conclusions: The study showed that clinical decision might be a very serious factor related to PTSS among healthcare professionals during the COVID-19. Clinical decision for patients with COVID-19 has a high experience rate and was considered to be a serious experience among healthcare professionals during the pandemic. As a countermeasure for the mental health of healthcare professionals during the COVID-19, it is important for healthcare professionals to take countermeasures for clinical decision for patients with COVID-19

Suprabasin-derived bioactive peptides identified by plasma peptidomics

Abstract Identification of low-abundance, low-molecular-weight native peptides using non-tryptic plasma has long remained an unmet challenge, leaving potential bioactive/biomarker peptides undiscovered. We have succeeded in efficiently removing high-abundance plasma proteins to enrich and comprehensively identify low-molecular-weight native peptides using mass spectrometry. Native peptide sequences were chemically synthesized and subsequent functional analyses resulted in the discovery of three novel bioactive polypeptides derived from an epidermal differentiation marker protein, suprabasin. SBSN_HUMAN[279–295] potently suppressed food/water intake and induced locomotor activity when injected intraperitoneally, while SBSN_HUMAN[225–237] and SBSN_HUMAN[243–259] stimulated the expression of proinflammatory cytokines via activation of NF-κB signaling in vascular cells. SBSN_HUMAN[225–237] and SBSN_HUMAN[279–295] immunoreactivities were present in almost all human organs analyzed, while immunoreactive SBSN_HUMAN[243–259] was abundant in the liver and pancreas. Human macrophages expressed the three suprabasin-derived peptides. This study illustrates a new approach for discovering unknown bioactive peptides in plasma via the generation of peptide libraries using a novel peptidomic strategy