Induction of human regulatory innate lymphoid cells from group 2 innate lymphoid cells by retinoic acid

BACKGROUND: Group 2 innate lymphoid cells (ILC2s) play critical roles in induction and exacerbation of allergic airway inflammation. Thus, clarification of the mechanisms that underlie the regulation of ILC2 activation has received significant attention. Although ILCs are divided into three major subsets that mirror helper effector T-cell subsets, counterpart subsets of regulatory T (Treg) cells have not been well characterized. OBJECTIVE: We sought to determine the factors that induce regulatory ILCs (ILCregs). METHODS: IL-10+ ILCregs induced from ILC2s by retinoic acid (RA) were analyzed using RNA-sequencing and flow cytometry. ILCregs were evaluated in human nasal tissues from healthy individuals and patients with chronic rhinosinusitis with nasal polyp (CRSwNP), and in lung tissues from house dust mite (HDM)- or saline-treated mice. RESULTS: RA induced IL-10 secretion by human ILC2s, but not type-2 cytokines. IL-10+ ILCregs, converted from ILC2s by RA stimulation, expressed a Treg-like signature with the expression of IL-10, CTLA-4 and CD25, with down regulated effector type 2-related markers such as CRTH-2 and ST2, and suppressed activation of CD4+ T cells and ILC2s. ILCregs were rarely detected in human nasal tissue from healthy individuals or lung tissues from saline-treated mice, but were increased in nasal tissues from patients with CRSwNP and in lung tissues from HDM-treated mice. Enzymes for RA synthesis were up-regulated in airway epithelial cells during type-2 inflammation in vivo and by IL-13 in vitro. CONCLUSION: We have identified a unique immune regulatory and anti-inflammatory pathway by which RA converts ILC2s to ILCregs. Interactions between airway epithelial cells and ILC2s play an important roles in the generation of ILCregs

Epithelioid granulomatous lesions express abundant programmed death ligand-1 (PD-L1): a discussion of adverse events in anti-PD-1 antibody-based cancer immunotherapy

The immune system is often called a double-edged sword, due to the inextricable link between cancer immunity and allergy/autoimmunity. Intriguingly, a growing number of cases have been reported in which PD-1 blockade triggers the exacerbation of tuberculosis (TB), an organ-invasive granulomatous disease caused by bacterial infection. As a result, the exacerbation of TB is now considered a severe adverse effect of nivolumab and pembrolizumab. In this letter, we report the strong expression of PD-L1 in epithelioid granulomatous lesions in tuberculosis, sarcoidosis, Crohn’s disease, and foreign body granuloma. In addition, we discussed the exacerbation of tuberculosis after anti-PD-1 antibody-based cancer immunotherapy

Assessment of cancer cell-expressed HLA class I molecules and their immunopathological implications

Immunotherapy using immune checkpoint inhibitors (ICIs) has shown superior efficacy compared with conventional chemotherapy in certain cancer types, establishing immunotherapy as the fourth standard treatment alongside surgical intervention, chemotherapy, and radiotherapy. In cancer immunotherapy employing ICIs, CD8-positive cytotoxic T lymphocytes are recognized as the primary effector cells. For effective clinical outcomes, it is essential that the targeted cancer cells express HLA class I molecules to present antigenic peptides derived from the tumor. However, cancer cells utilize various mechanisms to downregulate or lose HLA class I molecules from their surface, resulting in evasion from immune surveillance. Correlations between prognosis and the integrity of HLA class I molecules expressed by cancer cells have been consistently found across different types of cancer. This paper provides an overview of the regulatory mechanisms of HLA class I molecules and their role in cancer immunotherapy, with a particular emphasis on the significance of utilizing pathological tissues to evaluate HLA class I molecules expressed in cancer cells.journal articl

Severe cytokine release syndrome resulting in purpura fulminans despite successful response to nivolumab therapy in a patient with pleomorphic carcinoma of the lung: a case report

Abstract Background Immune checkpoint inhibitors (ICIs) have provided more options in the treatment of lung cancer. However, ICIs can cause several unfavorable reactions generally referred to as immune-related adverse effects. Case presentation In this report, we present the case of a 52-year-old woman with successful regression of pleomorphic carcinoma of the lung following nivolumab therapy. She developed purpura fulminans (PF) ultimately resulting in amputation of both lower extremities. Blood tests revealed thrombocytopenia with increased serum soluble IL-2 receptor, ferritin, and triglyceride levels suggesting hemophagocytic lymphohistiocytosis (HLH). In addition, serum A disintegrin-like and metalloproteinase with thrombospondin type 1 motifs 13 activity was decreased, suggesting thrombotic thrombocytopenic purpura (TTP). Further detailed analysis revealed severe hypercytokinemia including increased levels of IL-1β, IL-6, IL-10, TNFα, IFNγ, and G-CSF. Conclusion The severe systemic inflammatory reaction and impaired peripheral circulation in this patient was attributed to excessive immunological effect induced by nivolumab resulting in cytokine release syndrome (CRS). This is the first report of a patient with multiple pathological conditions including HLH, TTP-like condition, and PF presumably arising from ICI-induced CRS. Further accumulating thoroughly investigated cases would lead to better understanding of the disease and development of reliable cancer immunotherapy

Direct platelet adhesion potentiates group 2 innate lymphoid cell functions

Background Platelets are thought to be involved in the pathophysiology of asthma, presumably through direct adhesion to inflammatory cells, including group 2 innate lymphoid cells (ILC2s). Here, we tried to elucidate the effects of platelet adhesion to ILC2s in vitro and in vivo, as well as the mechanisms involved. Methods Alternaria-induced ILC2-dependent airway inflammation models using wild-type and c-mpl−/− mice were evaluated. Both purified CD41+ and CD41−ILC2s were cultured with IL-2 and IL-33 to determine in vitro Type 2 (T2) cytokine production and cell proliferation. RNA-seq data of flow-cytometry-sorted CD41+ and CD41−ILC2s were used to isolate ILC2-specific genes. Flow cytometry was performed to determine the expression of CD41 and adhesion-related molecules on ILC2s in both mouse and human tissues. Results T2 inflammation and T2 cytokine production from ILC2s were significantly reduced in the c-mpl−/− mice compared to wild-type mice. Platelet-adherent ILC2s underwent significant proliferation and showed enhanced T2 cytokine production when exposed to IL-2 and IL-33. The functions of ILC2-specific genes were related to cell development and function. Upstream regulator analysis identified 15 molecules, that are thought to be involved in ILC2 activation. CD41 expression levels were higher in ILC2s from human PBMCs and mouse lung than in those from secondary lymphoid tissues, but they did not correlate with the P-selectin glycoprotein ligand-1 or CD24 expression level. Conclusion Platelets spontaneously adhere to ILC2s, probably in the peripheral blood and airways, thereby potentiating ILC2s to enhance their responses to IL-33

Detection of specific gene rearrangements by fluorescence in situ hybridization in 16 cases of clear cell sarcoma of soft tissue and 6 cases of clear cell sarcoma-like gastrointestinal tumor

Abstract Background Clear cell sarcoma of soft tissue (CCSST) and clear cell sarcoma-like gastrointestinal tumor (CCSLGT) are malignant mesenchymal tumors that share some pathological features, but they also have several different characteristics. They are well known to express chimeric fusions of Ewing sarcoma breakpoint region 1 (EWSR1) and cAMP response element-binding protein (CREB) family members; namely, EWSR1-activating transcription factor 1 (ATF1) and EWSR1-CREB1. In addition, recent studies have suggested the presence of other fusions. Methods We used fluorescence in situ hybridization to detect specific rearrangements including EWSR1, ATF1, CREB1, and cAMP response element modulator (CREM) in 16 CCSST and 6 CCSLGT cases. We also used reverse transcription polymerase chain reaction (RT-PCR) to detect specific chimeric fusions of EWSR1-ATF1 and EWSR1-CREB1 using fresh tumor samples in available cases. Results A total of 15 of 16 CCSST cases (93.8%) had EWSR1 rearrangement, of which 11 (68.8%) also had ATF1 rearrangement, suggestive of the presence of EWSR1-ATF1 fusions. One CCSST case (6.3%) was found to have EWSR1 and CREM rearrangements, and 4 of 6 CCSLGT cases (66.7%) had EWSR1 rearrangement, of which 2 (33.3%) showed ATF1 rearrangement and the other 2 cases (33.3%) showed CREB1 rearrangement. These cases most likely had EWSR1-ATF1 and EWSR1-CREB1 fusions, respectively. RT-PCR was performed in 8 available cases, including 6 CCSSTs and 2 CCSLGTs. All CCSSTs showed EWSR1-ATF1 fusions. Among the 2 CCSLGT cases, one had EWSR1-ATF1 fusion and the other had EWSR1-CREB1 fusion. Conclusions Rearrangements of EWSR1 and ATF1 or EWSR1-ATF1 fusion were predominantly found in CCSST, whereas those of EWSR1 and CREB1 or EWSR1-CREB1 tended to be detected in CCSLGT. A novel CREM fusion was also detected in a few cases of CCSST and CCSLGT. The cases in which EWSR1 rearrangement was detected without definitive partner genes should be considered for the presence of CREM rearrangement

気管支上皮のバリア維持におけるCpG-DNAの役割

生体の恒常性は上皮が形成するバリアが生体の内と外を隔てることによって維持されている．近年の報告によって気管支喘息患者の気管支上皮バリアは破壊されていることが明らかとなってきた．上皮バリアの破綻は外来抗原や微生物の生体内へのアクセスを促進し，抗原感作と免疫反応の発動を引き起こす．さらに免疫反応とバリア破壊は増悪ループを形成し，組織リモデリングに至ると考えられている．従って気管支喘息の発症と慢性化メカニズムの解明において上皮バリアの制御機構を明らかとすることは必須である．Toll-like receptor 9のリガンドであるCpG-DNAは制御性T細胞や1型ヘルパーT細胞の誘導を通して気管支喘息の病態をコントロールすると報告されていたが，上皮バリアに対する影響は知られていなかった．本研究では気相・液相境界培養法を用いて分化させた気管支上皮をCpG-DNAで刺激し経上皮電気抵抗と蛍光標識デキストランの透過量によってバリア機能を評価した．その結果，CpG-DNAにて刺激された気管支上皮のバリアは増強された．気管支喘息の病態形成に中心的役割を示すIL-13は上皮バリアを減弱させることが報告されているが，CpG-DNAはIL-13によるバリア障害に対して拮抗的に働いていた．また，CpG-DNAは気管支喘息上皮の障害されたバリアを修復した．これらの結果は気管支喘息の発症における衛生仮説を裏付けるものであり，CpG-DNAは気管支喘息の予防と治療に有効と考えられる