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Background: The efficacy of immune checkpoint inhibitors (ICIs) in pleural mesothelioma has recently been established. The response to ICIs can be predicted by quantitative analysis of cells and their spatial distribution in the tumor microenvironment (TME). However, the detailed composition of the TME in pleural mesothelioma has not been reported. We evaluated the association between the TME and response to ICIs in this cancer. Methods: A retrospective analysis of 22 pleural mesothelioma patients treated with nivolumab in different centers was performed using surgical specimens. Four patients had a partial response to nivolumab (response group) and 18 patients had stable or progressive disease (nonresponse group). The number of CD4, CD8, FoxP3, CK, and PD‐L1 positive cells, cell density, and cell‐to‐cell distance were analyzed by multiplex immunofluorescence. Results: PD‐L1 expression did not differ significantly between the response and nonresponse groups. The density of total T cells and of CD8+ T cells was significantly higher in the response than in the nonresponse group. CD8+ T cells were more clustered and located closer to tumor cells, whereas regulatory T cells were located further from tumor cells in the response than in the nonresponse group. Conclusions: High density and spatial proximity of CD8+ T cells to tumor cells were associated with better response to nivolumab, whereas the proximity of regulatory T cells to tumor cells was associated with worse response, suggesting that the distinct landscape of the TME could be a potential predictor of ICI efficacy in pleural mesothelioma. [ABSTRACT FROM AUTHOR]

Introduction: Contact hypersensitivity (CHS), a type of delayed‐type hypersensitivity, is induced by hapten exposure to the skin and mucosa. We previously reported that, in a murine model of CHS, the vaginal mucosa (VM) sensitization showed lower T‐cell responses as compared with the abdominal skin sensitization. To investigate mechanisms of impaired CHS by the VM sensitization, we compared migration of hapten‐captured dendritic cells (DCs) in the draining lymph nodes (dLNs) and recruitment of DCs at the sensitized local sites. Methods: Fluorescein isothiocyanate (FITC) or 2,4‑dinitrofluorobenzene (DNFB) was used as hapten, and migration of FITC+ DCs in the dLNs and local recruitment of MHC class II+ and CD11c+ cells were compared between abdominal skin and VM sensitization by flow cytometric analyses and immunohistochemistry. Expression of tumor growth factor (TGF)‐β at mRNA and protein levels, and local recruitment of CD206+ cells were examined after VM sensitization. Results: VM sensitization showed less numbers of FITC+MHC class IIhighCD11c+ migratory DCs in the dLNs at 6 and 24 h, as compared with skin sensitization. Both skin and VM sensitization induced the recruitment of dermal/submucosal DCs at 6 h, but the number of submucosal DCs in the VM was significantly decreased at 24 h. VM showed persistently higher mRNA levels of TGF‐β2/β3 expression than those of the skin before and after sensitization. In the VM sensitization, increment of CD206+MHC class II+ cells was observed especially at the deep lamina propria at 24 h. Most of CD206+ cells were also positive for the binding to Fc chimeric TGF‐β receptor that interacts with all TGF‐β isoforms, suggesting TGF‐β expression. Conclusion: DC migration to dLNs and localization of DCs at the sensitized sites are limited in the VM sensitization. Our results suggest that the existence of TGF‐β‐expressing CD206+ cells may contribute less sensitization ability and CHS responses in the VM. [ABSTRACT FROM AUTHOR]

Background: The immune checkpoint programmed cell death 1 (PD-1): PD-1 ligand 1 (PD-L1) pathway plays a crucial role in maintaining immune tolerance and preventing tissue damages by excessive immune responses. PD-L1 is physiologically expressed and upregulated in keratinocytes (KCs) in the oral cavity. We here investigated the contribution of PD-L1 that was overexpressed in gingival basal KCs in a ligature-induced periodontitis model.Methods: Wild-type (WT) BALB/c and K14/PD-L1 transgenic (tg) mice, in which PD-L1 was overexpressed in basal KCs under control of the keratin 14 promoter, were used. To induce periodontitis, a 9-0 silk ligature was placed around the upper right second molar, and lipopolysaccharide from Porphyromonas gingivalis was applied on the suture. Gingival tissues were collected on day 7, after which histological analyses were performed, including by hematoxylin and eosin and tartrate-resistant acid phosphate staining (TRAP) and quantitative PCR for proinflammatory cytokines and bone metabolism-related genes. Alveolar bone loss at 7 weeks after ligature placement was assessed by micro-computed tomography analysis.Results: PD-L1 was overexpressed in the basal KCs of all gingival epithelia in K14/PD-L1tg mice. Early ligature-induced periodontal inflammation, as assessed based on histological changes, elevation of proinflammatory cytokine (IL-1β, IL-6, TNF-α) expression, periodontal ligament degeneration, and osteoclastogenesis as assessed by Rankl and Opg expression and TRAP+ cells, was markedly impaired in K14/PD-L1tg mice. Alveolar bone resorption at a late time point was also clearly minimized in K14/PD-L1tg mice.Conclusion: Overexpression of PD-L1 in gingival basal keratinocytes in K14/PD-L1tg mice reduces periodontal inflammation and alveolar bone resorption in a ligature-induced periodontitis model. [ABSTRACT FROM AUTHOR]

Background: The efficacy of immune checkpoint inhibitors (ICIs) in pleural mesothelioma has recently been established. The response to ICIs can be predicted by quantitative analysis of cells and their spatial distribution in the tumor microenvironment (TME). However, the detailed composition of the TME in pleural mesothelioma has not been reported. We evaluated the association between the TME and response to ICIs in this cancer., Methods: A retrospective analysis of 22 pleural mesothelioma patients treated with nivolumab in different centers was performed using surgical specimens. Four patients had a partial response to nivolumab (response group) and 18 patients had stable or progressive disease (nonresponse group). The number of CD4, CD8, FoxP3, CK, and PD-L1 positive cells, cell density, and cell-to-cell distance were analyzed by multiplex immunofluorescence., Results: PD-L1 expression did not differ significantly between the response and nonresponse groups. The density of total T cells and of CD8 + T cells was significantly higher in the response than in the nonresponse group. CD8 + T cells were more clustered and located closer to tumor cells, whereas regulatory T cells were located further from tumor cells in the response than in the nonresponse group., Conclusions: High density and spatial proximity of CD8 + T cells to tumor cells were associated with better response to nivolumab, whereas the proximity of regulatory T cells to tumor cells was associated with worse response, suggesting that the distinct landscape of the TME could be a potential predictor of ICI efficacy in pleural mesothelioma., (© 2023 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

T-cell responses are fine-tuned by positive and negative co-signal molecules expressed on immune cells and adjacent tissues. VSIG4 is a newly identified member of the B7 family of ligands, which negatively regulates innate inflammatory and CD4 + T cell-mediated responses. However, little is known about the direct effects of VSIG4, which are exerted through an unidentified counter-receptor on CD8 + T cells. We investigated the binding of the VSIG4-Ig fusion protein during CD8 + T cell activation, and the functional involvement of VSIG4 pathway, using VSIG4-Ig and VSIG4-transfectants. VSIG4-Ig binding to CD8 + T cells was temporally observed in the CD44 high phenotype during initial activation. VSIG4-Ig binding was observed earlier than the induction of PD-1, LAG3, and TIM-3, which are immune checkpoint receptors for exhausted CD8 + T cells. Immobilized VSIG4-Ig inhibited anti-CD3/CD28 mAb-induced CD8 + T cell activation, as indicated by proliferation and IFN-γ production, similar to the downregulation of T-bet and Eomesodermin transcription factors. VSIG4 on FcγR + P815 or specific antigen-presenting E.G7 cells inhibited the generation of effector CD8 + T cells, as indicated by proliferation, IFN-γ and TNF-α expression, and granule degradation, compared to parental cells. However, the window for the regulatory function of VSIG4 was narrow and dependent on the strength of TCR (and CD28)-mediated signals. Our results suggested that VSIG4 directly delivers co-inhibitory signals via an as-yet unidentified counter-receptor on activated CD8 + T cells. VSIG4-mediated CD8 + T cell tolerance might contribute to the steady-state maintenance of homeostasis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interest or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)