Inducible T-cell Costimulator Research Articles

Clinical Insights Into Novel Immune Checkpoint Inhibitors

The success of immune checkpoint inhibitors (ICIs), notably anti-cytotoxic T lymphocyte associated antigen-4 (CTLA-4) as well as inhibitors of CTLA-4, programmed death 1 (PD-1), and programmed death ligand-1 (PD-L1), has revolutionized treatment options for solid tumors. However, the lack of response to treatment, in terms of de novo or acquired resistance, and immune related adverse events (IRAE) remain as hurdles. One mechanisms to overcome the limitations of ICIs is to target other immune checkpoints associated with tumor microenvironment. Immune checkpoints such as lymphocyte activation gene-3 (LAG-3), T cell immunoglobulin and ITIM domain (TIGIT), T cell immunoglobulin and mucin-domain containing-3 (TIM-3), V-domain immunoglobulin suppressor of T cell activation (VISTA), B7 homolog 3 protein (B7-H3), inducible T cell costimulatory (ICOS), and B and T lymphocyte attenuator (BTLA) are feasible and promising options for treating solid tumors, and clinical trials are currently under active investigation. This review aims to summarize the clinical aspects of the immune checkpoints and introduce novel agents targeting these checkpoints.

Engagement of ICOS in tissues promotes establishment of CD8+ tissue-resident memory T cells

Abstract Resident memory T cells (TRM) provide localized protective immunity in non-lymphoid tissues, but the signals and interactions within non-lymphoid tissues involved in generating TRM are incompletely defined. Inducible T-cell costimulator (ICOS) is a costimulatory molecule with well elaborated roles in regulating differentiation of CD4+ T cell populations, its function in CD8+ T cells is largely unexplored. With acute infection models, we found that ICOS-deficient CD8+ T cells showed minimal defects in the initial effector expansion and the generation of recirculating memory subsets. However, consistent with its high expression in TRM, ICOS deficiency significantly compromised the establishment of CD8+ TRM cells in diverse non-lymphoid tissues. We further confirmed that rather than pre-programming the TRM fate during initial T cell priming, the interaction between ICOS ligand (ICOSL) and ICOS in the non-lymphoid tissues during CD8+ T cell recruitment is critical for efficient tissue retention and acquisition of tissue residency signatures. ICOS signaling through PI3K pathway is key for TRM generation and ICOS stimulation promotes downregulation of KLF2, a transcription factor that regulates T cell trafficking, in CD8+ T cells after entering non-lymphoid tissues. Altogether, our data illustrate that engagement of ICOS is one of the critical local costimulatory cues that promote the establishment of tissue-resident populations, with potential implication for therapeutic manipulation.

A novel subset of follicular helper-like MAIT cells has capacity for B cell help and antibody production in the mucosa.

Abstract Mucosal-associated invariant T (MAIT) cells are innate-like T lymphocytes that respond to conserved microbial metabolites presented on the evolutionarily conserved MHC class I-related protein, MR1. MAIT cells are enriched in the mucosa and aid in protection against bacterial pathogens via release of inflammatory cytokines and cytotoxic molecules. Recent evidence suggests MAIT cells are capable of providing B cell help in vitro and in vivo. In this study, we used primary human samples and mouse models to uncover the role of MAIT cells in B cell help at the mucosa. Here we describe a novel population of CXCR5+ T follicular helper (Tfh)-like MAIT cells (MAITfh) that are enriched in human mucosal lymphoid tissues. Using in vitro culture assays and fluorescence imaging, we found that MAITfh cells preferentially locate within germinal centers in human tonsils and express the canonical Tfh transcription factor, B-cell lymphoma 6 (BCL-6), co-stimulatory markers, inducible T cell costimulator (ICOS), and programmed death receptor 1 (PD-1), and cytokines, interleukin (IL)-21, IL-10, and BAFF. Furthermore, we investigate the sufficiency of MAIT cells to aid in antibody mediated immunity in vivo using a mouse model of MAIT adoptive transfer followed by mucosal challenge with live Vibrio cholerae. We show that adoptive transfer of MAIT cells into αβ T cell deficient mice promotes B cell differentiation and increased serum V. cholerae-specific IgA and bactericidal responses. Our data demonstrate the capacity of MAIT cells to participate in adaptive immune responses at the mucosa, and suggest MAIT cells may be potential targets to improve mucosal vaccines.

ICOS signaling limits regulatory T cell accumulation and function in visceral adipose tissue.

A unique population of Foxp3+ regulatory T cells (TRs) resides in visceral adipose tissue (VAT) that regulates adipose inflammation and helps preserve insulin sensitivity. Inducible T cellco-stimulator (ICOS) is highly expressed on effector (e)TRs that migrate to nonlymphoid tissues, and contributes to their maintenance and function in models of autoimmunity. In this study, we report an unexpected cell-intrinsic role for ICOS expression and downstream phosphoinositide 3-kinase (PI3K) signaling in limiting the abundance, VAT-associated phenotype, and function of TRs specifically in VAT. Icos-/- mice and mice expressing a knock-in form of ICOS that cannot activate PI3K had increased VAT-TR abundance and elevated expression of canonical VAT-TR markers. Loss of ICOS signaling facilitated enhanced accumulation of TRs to VAT associated with elevated CCR3 expression, and resulted in reduced adipose inflammation and heightened insulin sensitivity in the context of a high-fat diet. Thus, we have uncovered a new and surprising molecular pathway that regulates VAT-TR accumulation and function.

Pattern of Tumor-Infiltrating Lymphocytes in Mixed Epithelial and Stromal Tumor of the Kidney: A Review of Five Cases.

Mixed epithelial and stromal tumor of the kidney (MESTK), a benign rare tumor with malignant transformation potential, is thought to be derived from fetal or immature cells originating from the mesonephric and Müllerian ducts. However, due to its rarity, little is known about the anti-tumor immune responses in MESTK. Herein, we present five cases of MESTK and evaluate the population of tumor-infiltrating lymphocytes (TILs) using a freshly obtained MESTK sample. Microscopically, TILs were scattered or clustered in large aggregates in the stroma in all five cases; furthermore, three cases exhibited heavy, large lymphocytic aggregates with no well-organized tertiary lymphoid structures with germinal centers. Flow cytometric analysis of TILs in one freshly obtained MESTK sample revealed that >40% of CD3+ T cells were effector memory Fas+CD28− γδ T cells expressing high levels of programmed cell death protein 1 and inducible T-cell co-stimulator, but low levels of CD44 and CD27. Most αß T cells exhibited a naïve phenotype. Additionally, we detected many activated class-switched CD21+CD27+ B cells as well as CD11chighIgMhigh marginal zone B-like and CD27−CD21−CD23− immunoglobulin (Ig)DhighIgMlow age-associated B-like cells. Collectively, for the first time, we report the immune microenvironment pattern of MESTK to oncogenic stress.

LAG-3-Expressing Tumor-Infiltrating T Cells Are Associated with Reduced Disease-Free Survival in Pancreatic Cancer.

Simple SummaryIn light of the majority of pancreatic cancer patients not responding to current immune checkpoint blockade, alternative immunotherapeutic targets need to be identified. In this study, we employed multiplex immunofluorescence to investigate the expression of co-stimulatory and inhibitory receptors by tumor-infiltrating T cells in human pancreatic cancer. A comprehensive analysis of the receptor pattern on tumor-infiltrating T cells is essential for the development of new therapeutic strategies, as well as personalized immunotherapy, to identify patients who are likely to benefit from targeting specific immune receptors.T cells are the predominant immune cell population in the pancreatic tumor microenvironment. High CD8+ and Th1-polarized CD4+ T cell infiltration is associated with prolonged survival in human pancreatic ductal adenocarcinoma (PDAC). However, the expression pattern of co-stimulatory and inhibitory receptors by PDAC-infiltrating T cells and their prognostic significance are not well defined. In this study, we employed multiplex immunofluorescence to investigate the intratumoral expression of the co-stimulatory receptor inducible T-cell co-stimulator (ICOS), the inhibitory receptors lymphocyte-activation gene 3 (LAG-3), programmed death 1 (PD-1), and V-domain immunoglobulin suppressor of T cell activation (VISTA) by tumor-infiltrating T cells (CD3) in a cohort of 69 patients with resected PDAC. T cells were enriched particularly within the stromal area and were highly heterogeneous across tumors. Further, T cells were associated with prolonged disease-free survival (DFS). However, LAG-3 expression by PDAC-infiltrating T cells was correlated with reduced DFS. Our study highlights the biological importance of LAG-3 expression by tumor-infiltrating T cells. LAG-3+ T cells may represent a novel prognostic marker and a particularly attractive target for immunotherapeutic strategies in PDAC.

The ubiquitin ligase Peli1 inhibits ICOS and thereby Tfh-mediated immunity

T follicular helper (Tfh) cells are crucial for regulating autoimmune inflammation and protective immunity against viral infection. However, the molecular mechanism controlling Tfh cell differentiation is poorly understood. Here, through two mixed bone marrow chimeric experiments, we identified Peli1, a T cell-enriched E3 ubiquitin ligase, as an intrinsic regulator that inhibits Tfh cell differentiation. Peli1 deficiency significantly promoted c-Rel-mediated inducible T-cell costimulator (ICOS) expression, and PELI1 mRNA expression was negatively associated with ICOS expression on human CD4+ T cells. Mechanistically, increased ICOS expression on Peli1-KO CD4+ T cells enhanced the activation of PI3K-AKT signaling and thus suppressed the expression of Klf2, a transcription factor that inhibits Tfh differentiation. Therefore, reconstitution of Klf2 abolished the differences in Tfh differentiation and germinal center reaction between WT and Peli1-KO cells. As a consequence, Peli1-deficient CD4+ T cells promoted lupus-like autoimmunity but protected against H1N1 influenza virus infection in mouse models. Collectively, our findings established Peli1 as a critical negative regulator of Tfh differentiation and indicated that targeting Peli1 may have beneficial therapeutic effects in Tfh-related autoimmunity or infectious diseases.

Increased circulating PD-1hiCXCR5- peripheral helper T cells are associated with disease severity of active ulcerative colitis patients

PurposeA recently identified population of T cells, phenotypically CD4+PD-1hiCXCR5−, has been firstly termed as peripheral helper T cells (Tph) and found to be pathogenic in autoimmune diseases. However, the potential role of Tph in ulcerative colitis (UC) remains unclear. We aim to investigate the changes of circulating Tph in UC patients and their potential significance in the pathogenesis of UC. MethodsTotally 68 UC patients and 34 age- and sex-matched healthy controls were enrolled. Circulating Tph and B cell subsets were analyzed by flow cytometry. Expressions of inducible T-cell co-stimulator (ICOS) on Tph cells were analyzed. Serum IL-4, IL-10, IL-12 and IL-21 were detected using ELISA. Correlation analyses were conducted between Tph cells and disease severity, functional B cell subsets and serum cytokines. ResultsBoth the frequency and absolute number of Tph were significantly increased in active UC patients and ICOS levels in Tph cells were also elevated, compared with remission UC patients and healthy controls. Tph and ICOS expression were significantly positively correlated with Mayo score and serum CRP in active UC patients, and were significantly decreased when achieving remission after treatment. Tph levels were correlated with new memory B cells, plasmablasts, serum IL-4 and IL-21. Meanwhile, serum IL-10 showed negative correlation while IL-12 exhibited positive correlation with circulating Tph cells in UC patients. ConclusionsCirculating Tph cells are elevated in active UC patients and are associated with the disease activity, which may contribute to the pathogenesis of UC.

A New PET Probe for Imaging Chimeric Antigen Receptor T Cells.

HomeRadiology: Imaging CancerVol. 3, No. 2 PreviousNext Research HighlightsFree AccessA New PET Probe for Imaging Chimeric Antigen Receptor T CellsGary D. LukerGary D. LukerGary D. LukerPublished Online:Mar 26 2021https://doi.org/10.1148/rycan.2021219004MoreSectionsPDF ToolsImage ViewerAdd to favoritesCiteTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinked In Take-Away Points■ Major Focus: To investigate the feasibility of imaging chimeric antigen receptor (CAR) T cells with a zirconium 89–labeled antibody targeted to inducible T-cell costimulator (ICOS or CD278).■ Key Result: ImmunoPET imaging of ICOS enabled the visualization of activated CAR T cells without affecting persistence or function of these cells in a mouse model of B-cell lymphoma.■ Impact: ImmunoPET with antibody detection of the endogenous activation marker ICOS provides a potentially general approach to image any CAR T-cell therapy.CAR T cells are a type of cancer therapy based on engineering a patient’s own T cells with a receptor for a specific protein target on cancer cells. After expansion of the cells in a laboratory, a patient receives an infusion of the engineered CAR T cells. For efficacy, the cells must migrate to tumors, proliferate, as well as become and remain activated to kill target cancer cells. CAR T cells have shown impressive successes in some blood cancers, such as B-cell malignancies, but efficacy remains limited in solid tumors. A major challenge in understanding successes and failures of CAR T-cell therapy is the ability to monitor these cells in vivo. Current methods rely on measuring numbers of cells in the circulation, but this approach does not reliably reflect actual migration of CAR T cells into a tumor.Simonetta and colleagues analyzed human and mouse CAR T cells and identified ICOS as a promising marker of activation to an antitumor state. The team labeled an antibody to ICOS with zirconium 89, providing a probe for PET imaging of CAR T cells in a mouse model of B-cell lymphoma. PET imaging showed greater accumulation of the immunoPET probe to ICOS in mouse bone marrow sites of lymphoma. Tracer doses of the immunoPET antibody did not affect persistence or function of CAR T cells as cancer immunotherapeutics. While the current study investigated therapy in mice, the study suggests that immunoPET imaging of ICOS could become a clinically translatable, general approach to monitor cancer therapy with a wide range of CAR T cells.Highlighted ArticleSimonetta F, Alam IS, Lohmeyer JK, et al. Molecular imaging of chimeric antigen receptor T cells by ICOS-ImmunoPET. Clin Cancer Res 2021;27:1058–1068. doi: https://doi.org/10.1158/1078-0432.CCR-20-2770Highlighted ArticleSimonetta F, Alam IS, Lohmeyer JK, et al. Molecular imaging of chimeric antigen receptor T cells by ICOS-ImmunoPET. Clin Cancer Res 2021;27:1058–1068. doi: https://doi.org/10.1158/1078-0432.CCR-20-2770 Crossref, Medline, Google ScholarArticle HistoryPublished online: Mar 26 2021 FiguresReferencesRelatedDetailsRecommended Articles CD38-targeted Immuno-PET of Multiple Myeloma: From Xenograft Models to First-in-Human ImagingRadiology2020Volume: 295Issue: 3pp. 606-615Nanotechnology for Cancer Imaging: Advances, Challenges, and Clinical OpportunitiesRadiology: Imaging Cancer2021Volume: 3Issue: 318F FDG PET/CT and Novel Molecular Imaging for Directing Immunotherapy in CancerRadiology2022Volume: 304Issue: 2pp. 246-264Identification of HER2-Positive Metastases in Patients with HER2-Negative Primary Breast Cancer by Using HER2-targeted 89Zr-Pertuzumab PET/CTRadiology2020Volume: 296Issue: 2pp. 370-378Radiotheranostics in Cancer Diagnosis and ManagementRadiology2018Volume: 286Issue: 2pp. 388-400See More RSNA Education Exhibits Immune Effector Cell Therapy for Solid Tumors: Opportunities for Interventional RadiologyDigital Posters2019When Things Go Wrong, Characteristic PET CT Patterns of Triple and Double-Hit Lymphoma; A Pictorial ReviewDigital Posters2018Imaging Biomarkers in Targeted Therapies: From Quantitative Imaging to RadiomicsDigital Posters2019 RSNA Case Collection Benign bone marrow stimulation RSNA Case Collection2020Primary Calvarial Lymphoma RSNA Case Collection2021Primary Bone LymphomaRSNA Case Collection2020 Vol. 3, No. 2 Metrics Altmetric Score PDF download

Selected Articles from This Issue

The addition of platinum to anthracycline-based neoadjuvant chemotherap. improves pathological responses in triple-negative breast cancer but also increases treatment toxicity. In the NeoSTOP randomized trial, Sharma and colleagues found that a carboplatin plus docetaxel (CbD) regimen yielded similar pathological response and survival rates as the anthracycline-containing regimen of carboplatin plus paclitaxel, followed by doxorubicin plus cyclophosphamide, but with a more favorable toxicity profile. The CbD regimen represents an effective alternative for patients who are not candidates for anthracyclines and may also serve as a good backbone for neoadjuvant de-escalation trials for triple-negative breast cancer.Combining checkpoint inhibitors with antiangiogenic agents holds promise for cancer treatment. In a prior phase I study, camrelizumab plus apatinib demonstrated encouraging activity in advanced hepatocellular carcinoma (HCC). To further study this combination, Xu and colleagues performed a phase II study of camrelizumab plus apatinib in patients with advanced HCC. The overall response rate was 34.3% in the first-line and 22.5% in the second-line setting. The 12-month survival rate was 74.7% and 68.2%, respectively. Serious adverse events were observed in 28.9% patients. Still, this work suggests that this combination warrants further study in patients with advanced HCC.Breast tumors with higher levels of cytotoxic T-cell infiltration have a better prognosis and response to preoperative chemotherapy. Oncolytic viruses such as talimogene laherparepvec (TVEC) cause selective lysis of tumor cells and trigger activation of antigen presenting cells to stimulate an antitumor immune response. Soliman and colleagues performed a phase I study of TVEC combined with neoadjuvant chemotherap. in patients with triple-negative breast cancer. This combination treatment led to a complete response in 55% of patients with manageable toxicity. Furthermore, evidence of decreased immunosuppression was observed. These results support further investigation of this regimen in further trials.Currently, effective strategies to monitor chimeric antigen receptor (CAR) T cells in tissue are lacking. Simonetta and colleagues assessed the utility of antibody-based PET (immunoPET) as a molecular imaging strategy to monitor CAR T cells in tissue. Inducible T-cell COStimulator (ICOS) was identified as a potential target for immunoPET. 89Zr-DFO-ICOS mAb PET-CT detected signal specifically in mice treated with CAR T cells. Importantly, ICOS-targeting antibodies did not affect CAR T-cell persistence or function. This work identifies ICOS-immunoPET imaging as a promising strategy for monitoring of CAR T-cell therapy; further study of this approach in a clinical setting is warranted.

Abstract PS4-14: Immunological analysis of the combination therapy of nivolumab, paclitaxel and bevacizumab in patients with HER2-negative MBC in NEWBEAT trial (WJOG9917BTR)

Abstract Background: Synergistic antitumor effect of combined anti-PD-1 antibody and anti-VEGF agent has been expected, based on previous preclinical data. We have conducted NEWBEAT trial to evaluate efficacy of triple combination regimen of nivolumab + paclitaxel + bevacizumab in patients (pts)with HR+ HER2- MBC or metastatic TNBC, and clinical results were presented in SABCS 2019. A biomarker study (WJOG9917BTR) was conducted to evaluate the VEGF and immune status of these patients. Methods: HER2-negative breast cancer patients in the NEWBEAT trial were enrolled. To explore the biomarkers for the triple combination treatment, immune status and its dynamics were evaluated with multicolor flowcytometry, multiplex ELISA in peripheral blood before and after treatment. Results: Among the 57 patients who were enrolled to the NEWBEAT trial, 50 patients were registered to the biomarker study. The expression of Ki67 and inducible T-cell co-stimulator (ICOS) on T cells increased after treatment, indicating induction of the T cell proliferation and activation. In responder (defined as patients with progression-free survival longer than 1 year, n = 30), the number of naïve CD4+ T cells at pretreatment were higher and effector memory CD4+ T cells were lower than non-responder. On the other hand, CD86+ myeloid DC at pretreatment were lower in non-responder pts. The median concentration of VEGF-A in serum before treatment was 116.065 pg/ml (range: 0-740.23) and decreased below 37 pg/ml at day 8 after treatment. Although serum VEGF-A level is inversely correlated with clinical outcome of pts with anti-PD-1 antibody in previous reports, in this trial VEGF-A high subgroup had better objective response than VEGF-A low subgroup, suggesting that blockade of VEGF by bevacizumab may overcome immunosuppression via VEGF signaling. Interestingly, in recurrent pts , the number of VEGFR-2+ CD4+ T cells / Monocyte were higher, and PD-L1+ CD4+ T cells / Monocyte / myeloid Dendritic Cell tended to be higher than in de novo stage IV pts. These results suggested that immune status of recurrent pts were more immunosuppressive than de novo stage IV pts, and that it might be more effective by the combination therapy to block the VEGF and PD-1 pathways. Moreover, the changes of immune status and dynamics on CD8+ T cells were not observed, suggesting that the therapeutic strategy of breast cancer might require the re-activation of CD8+ effector T cells through the stimulation of antigen-presenting cells followed by modification of CD4+ helper T cells.Conclusions: Our analysis showed the different immune status depending stage, subtype and response in advanced breast cancer pts. The dynamic decrease of serum VEGF-A concentration and high expression of VEGFR-1 or VEGFR-2 in the immune suppressive cells in advanced breast cancer pts suggested that combination treatment with bevacizumab might clinically overcome the immune suppression via inhibition of VEGF-A. (UMIN000029590) Citation Format: Yukinori Ozaki, Shigehisa Kitano, Junji Tsurutani, Tsutomu Iwasa, Masato Takahashi, Toru Mukohara, Norikazu Masuda, Manabu Futamura, Hironobu Minami, Koji Matsumoto, Hidetaka Kawabata, Makiko Yamashita, Kenichi Yoshimura, Toshimi Takano. Immunological analysis of the combination therapy of nivolumab, paclitaxel and bevacizumab in patients with HER2-negative MBC in NEWBEAT trial (WJOG9917BTR) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS4-14.

Molecular Imaging of Chimeric Antigen Receptor T Cells by ICOS-ImmunoPET.

Immunomonitoring of chimeric antigen receptor (CAR) T cells relies primarily on their quantification in the peripheral blood, which inadequately quantifies their biodistribution and activation status in the tissues. Noninvasive molecular imaging of CAR T cells by PET is a promising approach with the ability to provide spatial, temporal, and functional information. Reported strategies rely on the incorporation of reporter transgenes or ex vivo biolabeling, significantly limiting the application of CAR T-cell molecular imaging. In this study, we assessed the ability of antibody-based PET (immunoPET) to noninvasively visualize CAR T cells. After analyzing human CAR T cells in vitro and ex vivo from patient samples to identify candidate targets for immunoPET, we employed a syngeneic, orthotopic murine tumor model of lymphoma to assess the feasibility of in vivo tracking of CAR T cells by immunoPET using the 89Zr-DFO-anti-ICOS tracer, which we have previously reported. Analysis of human CD19-CAR T cells during activation identified the Inducible T-cell COStimulator (ICOS) as a potential target for immunoPET. In a preclinical tumor model, 89Zr-DFO-ICOS mAb PET-CT imaging detected significantly higher signal in specific bone marrow-containing skeletal sites of CAR T-cell-treated mice compared with controls. Importantly, administration of ICOS-targeting antibodies at tracer doses did not interfere with CAR T-cell persistence and function. This study highlights the potential of ICOS-immunoPET imaging for monitoring of CAR T-cell therapy, a strategy readily applicable to both commercially available and investigational CAR T cells.See related commentary by Volpe et al., p. 911.

Different Characteristics of Childhood Asthma Related to Polyhexamethylene Guanidine Exposure

Rationale: Exposure to humidifier disinfectants (HDs) can increase the risk of asthma, but the characteristics of HD-related asthma are currently unclear. Polyhexamethylene guanidine (PHMG)-containing HD was the most commonly used and the most frequently associated with HD-associated lung injury. Objectives: To investigate the characteristics of PHMG-induced asthma. Methods: This general population-based birth cohort study used data from the Panel Study of Korean Children from 2008 (n = 846). Spirometry, bronchial provocation tests, detailed history recording, and physical examinations were performed on 7-year-old patients (n = 362). Exploratory analysis of plasma proteomics was performed. Results: Compared with the healthy control group, forced expiratory volume in 1 second was the lowest in PHMG-exposed asthma group (z-score = -0.806; 95% confidence interval, -1.492 to -0.119). The positive rate of bronchial hyperresponsiveness was lower in children with PHMG-exposed asthma compared with children with asthma without HD exposure (13.3% vs. 47.4%). Long-term exposure to low-intensity PHMG before the age of 3 years was associated with asthma symptoms. Periostin was higher in subjects with asthma without HD exposure compared with the healthy control subjects. The inducible T-cell costimulator ligand and hepatocyte growth factor activator werelower in PHMG-exposed asthma compared with asthma without exposure. Hepatocyte growth factor activator had a positive correlation with forced vital capacity (z-score) in asthma with PHMG exposure (r = 0.78; P < 0.01). Conclusions: The asthma associated with low-intensity exposure to PHMG is characterized by lower lung function, lower positive rates of bronchial hyperresponsiveness, and varied distributions of plasma proteins. These findings suggest that asthma related to PHMG exposure may constitute a different mechanism of asthma pathophysiology.

Immune Skew of Circulating Follicular Helper T Cells Associates With Myasthenia Gravis Severity.

ObjectiveTo clarify functional alterations of follicular helper T cells (Tfh) in myasthenia gravis (MG) because Tfh play important roles in helping B cells generate antibody-producing cells.MethodsA total of 24 immunotherapy-naive patients with anti–acetylcholine receptor (AchR) antibody–positive MG and 18 age-matched healthy subjects (HS) were enrolled. Samples from 6 patients were available for posttreatment analysis. Subsets of circulating Tfh (cTfh) and B cells were identified by flow cytometry analysis of surface molecules. Cytokine production by isolated cTfh subsets from 5 patients with MG and 5 HS was measured in vitro. Analysis was performed to examine the correlation between the frequency of cTfh subsets and that of plasmablasts and between cTfh subsets and the quantitative MG score.ResultscTfh increased with elevated expression of inducible T-cell costimulator (ICOS) in patients with MG. cTfh shifted to Th2 and Th17 over Th1 in MG. ICOShighcTfh produced significantly higher levels of interleukin (IL)-21, IL-4, and IL-17A than ICOSlow cTfh only in patients with MG. The frequency of cTfh within CD4 T cells was more closely associated with disease severity than the serum anti-AchR antibody titer and frequency of plasmablasts within B cells. Abnormalities of cTfh were improved after immunotherapy in parallel with clinical improvement.ConclusionsAlternation of cTfh is a key feature in the development of MG and may become a biomarker for disease severity and therapeutic efficacy.Classification of EvidenceThis study provides Class II evidence that the level of cTfh is associated with disease severity in patients with MG.

Tissue-resident PSGL1loCD4+ T cells promote B cell differentiation and chronic graft-versus-host disease-associated autoimmunity.

CD4+ T cell interactions with B cells play a critical role in the pathogenesis of systemic autoimmune diseases such as systemic lupus and chronic graft-versus-host disease (cGVHD). Extrafollicular CD44hiCD62LloPSGL1loCD4+ T cells (PSGL1loCD4+ T cells) are associated with the pathogenesis of lupus and cGVHD, but their causal role has not been established. With murine and humanized MHC-/-HLA-A2+DR4+ murine models of cGVHD, we showed that murine and human PSGL1loCD4+ T cells from GVHD target tissues have features of B cell helpers with upregulated expression of programmed cell death protein 1 (PD1) and inducible T cell costimulator (ICOS) and production of IL-21. They reside in nonlymphoid tissues without circulating in the blood and have features of tissue-resident memory T cells with upregulated expression of CD69. Murine PSGL1loCD4+ T cells from GVHD target tissues augmented B cell differentiation into plasma cells and production of autoantibodies via their PD1 interaction with PD-L2 on B cells. Human PSGL1loCD4+ T cells were apposed with memory B cells in the liver tissues of humanized mice and cGVHD patients. Human PSGL1loCD4+ T cells from humanized GVHD target tissues also augmented autologous memory B cell differentiation into plasma cells and antibody production in a PD1/PD-L2-dependent manner. Further preclinical studies targeting tissue-resident T cells to treat antibody-mediated features of autoimmune diseases are warranted.

Inhibitors of the Transcription Factor STAT3 Decrease Growth and Induce Immune Response Genes in Models of Malignant Pleural Mesothelioma (MPM).

Simple SummaryMalignant pleural mesothelioma (MPM) is characterized by the lack of effective long-term treatments and highly prevalent drug resistance. The paucity of potential therapeutic targets has led to dismal prognosis. We have examined the functional role of the signal transducer and activator of transcription 3 (STAT3) transcription factor in MPM. Even though highly specific STAT3 inhibitors have not yet come to fruition, we performed experiments targeting STAT3 expression and subsequently supported these experiments with small molecule drugs that were previously validated to target STAT3-dependent activation mechanisms. These drugs are United States Food and Drug Administration (FDA)-approved and showed efficacy in preclinical models of MPM at concentrations that can safely be achieved in humans. We also identified genes that strongly support the essential role of STAT3 in cell growth and are consistent with a role of STAT3 in immune suppression. Overall, the results establish a central role for STAT3 in tumor growth and encourage further expedient development of STAT3 pathway inhibitors for clinical use.Malignant pleural mesothelioma (MPM) is an aggressive cancer defined by loss-of-function mutations with few therapeutic options. We examined the contribution of the transcription factor Signal transducer and activator of transcription 3 (STAT3) to cell growth and gene expression in preclinical models of MPM. STAT3 is activated in a variety of tumors and is thought to be required for the maintenance of cancer stem cells. Targeting STAT3 using specific small hairpin RNAs (shRNAs) or with the pharmacologic inhibitors atovaquone or pyrimethamine efficiently reduced cell growth in established cell lines and primary-derived lines while showing minimal effects in nontransformed LP9 mesothelial cells. Moreover, atovaquone significantly reduced viability and tumor growth in microfluidic cultures of primary MPM as well as in an in vivo xenotransplant model. Biological changes were linked to modulation of gene expression associated with STAT3 signaling, including cell cycle progression and altered p53 response. Reflecting the role of STAT3 in inducing localized immune suppression, using both atovaquone and pyrimethamine resulted in the modulation of immunoregulatory genes predicted to enhance an immune response, including upregulation of ICOSLG (Inducible T-Cell Costimulator Ligand or B7H2). Thus, our data strongly support a role for STAT3 inhibitors as anti-MPM therapeutics.

The role of CD28 in adult T-cell leukaemia/lymphoma.

The role of CD28 in adult T-cell leukaemia/lymphoma.

Modelling of Immune Checkpoint Network Explains Synergistic Effects of Combined Immune Checkpoint Inhibitor Therapy and the Impact of Cytokines in Patient Response.

Simple SummaryThe future of cancer immunotherapy relies on a combination of individually targeted therapies. However, a lot of experiments are needed to define the most effective combinations of drugs. A computational and modelling approach could help reduce the number of experiments and suggest optimal treatments to test. This article presents a logical model of T cell activation influenced by immune checkpoints, and explores the effect of these checkpoints, suggests mechanisms that would explain why some treatments might be better suited than others. The model includes not only programmed cell death protein 1 (PD1) and cytotoxic T-lymphocyte-associated protein 4 (CTL4) downstream pathways but also those of other immune checkpoints such as T cell immunoglobulin and ITIM (immunoreceptor tyrosine-based inhibition motif) domain (TIGIT), lymphocyte activation gene 3 (LAG3), T cell immunoglobulin and mucin domain-containing protein 3 (TIM3), cluster of differentiation 226 (CD226), inducible T-cell costimulator (ICOS), and tumour necrosis factor receptors (TNFRs).After the success of the new generation of immune therapies, immune checkpoint receptors have become one important center of attention of molecular oncologists. The initial success and hopes of anti-programmed cell death protein 1 (anti-PD1) and anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA4) therapies have shown some limitations since a majority of patients have continued to show resistance. Other immune checkpoints have raised some interest and are under investigation, such as T cell immunoglobulin and ITIM (immunoreceptor tyrosine-based inhibition motif) domain (TIGIT), inducible T-cell costimulator (ICOS), and T cell immunoglobulin and mucin domain-containing protein 3 (TIM3), which appear as promising targets for immunotherapy. To explore their role and study possible synergetic effects of these different checkpoints, we have built a model of T cell receptor (TCR) regulation including not only PD1 and CTLA4, but also other well studied checkpoints (TIGIT, TIM3, lymphocyte activation gene 3 (LAG3), cluster of differentiation 226 (CD226), ICOS, and tumour necrosis factor receptors (TNFRs)) and simulated different aspects of T cell biology. Our model shows good correspondence with observations from available experimental studies of anti-PD1 and anti-CTLA4 therapies and suggest efficient combinations of immune checkpoint inhibitors (ICI). Among the possible candidates, TIGIT appears to be the most promising drug target in our model. The model predicts that signal transducer and activator of transcription 1 (STAT1)/STAT4-dependent pathways, activated by cytokines such as interleukin 12 (IL12) and interferon gamma (IFNG), could improve the effect of ICI therapy via upregulation of Tbet, suggesting that the effect of the cytokines related to STAT3/STAT1 activity is dependent on the balance between STAT1 and STAT3 downstream signalling.

Functional differentiation and regulation of follicular T helper cells in inflammation and autoimmunity.

Follicular T helper (TFH ) cells are specialized T cells that support B cells, which are essential for humoral immunity. TFH cells express the transcription factor B-cell lymphoma 6 (Bcl-6), chemokine (C-X-C motif) receptor (CXCR) 5, the surface receptors programmed cell death protein 1 (PD-1) and inducible T-cell costimulator (ICOS), the cytokine IL-21 and other molecules. The activation, proliferation and differentiation of TFH cells are closely related to dynamic changes in cellular metabolism. In this review, we summarize the progress made in understanding the development and functional differentiation of TFH cells. Specifically, we focus on the regulatory mechanisms of TFH cell functional differentiation, including regulatory signalling pathways and the metabolic regulatory mechanisms of TFH cells. In addition, TFH cells are closely related to immune-associated diseases, including infections, autoimmune diseases and cancers.

Unique expansion of IL-21+ Tfh and Tph cells under control of ICOS identifies Sjögren’s syndrome with ectopic germinal centres and MALT lymphoma

ObjectivesTo explore the relevance of T-follicular-helper (Tfh) and pathogenic peripheral-helper T-cells (Tph) in promoting ectopic lymphoid structures (ELS) and B-cell mucosa-associated lymphoid tissue (MALT) lymphomas (MALT-L) in Sjögren’s syndrome (SS)...