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MUC1 is a tumour-associated antigen expressed by many solid tumours, including non-small-cell lung cancer. TG4010 is a modified vaccinia Ankara expressing MUC1 and interleukin 2. In a previous study, TG4010 combined with chemotherapy showed activity in non-small-cell lung cancer and the baseline value of CD16, CD56, CD69 triple-positive activated lymphocytes (TrPAL) was shown to be potentially predictive of TG4010 efficacy. In this phase 2b part of the phase 2b/3 TIME trial, we further assess TG4010 in combination with first-line chemotherapy and use of the TrPAL biomarker in this setting. In this phase 2b part of a randomised, double-blind, placebo-controlled, phase 2b/3 trial, we recruited previously untreated patients aged 18 years or older with stage IV non-small-cell lung cancer without a known activating EGFR mutation and with MUC1 expression in at least 50% of tumoural cells. Patients were randomly allocated (1:1) by an external service provider to subcutaneous injections of 108 plaque-forming units of TG4010 or placebo from the beginning of chemotherapy every week for 6 weeks and then every 3 weeks up to progression, discontinuation for any reason, or toxic effects, stratified according to baseline value of TrPAL (≤ or > the upper limit of normal [ULN]) and, in addition, a dynamic minimisation procedure was used, taking into account chemotherapy regimen, histology, addition or not of bevacizumab, performance status, and centre. Patients, site staff, monitors, the study funder, data managers, and the statistician were masked to treatment identity. The primary endpoint was progression-free survival, assessed every 6 weeks, to validate the predictive value of the TrPAL biomarker. If patients with TrPAL values of less than or equal to the ULN had a Bayesian probability of more than 95% that the true hazard ratio (HR) for progression-free survival was less than 1, and if those with TrPAL values of greater than the ULN had a probability of more than 80% that the true HR for progression-free survival was more than 1, the TrPAL biomarker would be validated. We did primary analyses in the intention-to-treat population and safety analyses in those who had received at least one dose of study drug and had at least one valid post-baseline safety assessment. Monitors, site staff, and patients are still masked to treatment assignment. This trial is registered with ClinicalTrials.gov, number NCT01383148. Between April 10, 2012, and Sept 12, 2014, we randomly allocated 222 patients (TG4010 and chemotherapy 111 [50%]; placebo and chemotherapy 111 [50%]). In the whole population, median progression-free survival was 5·9 months (95% CI 5·4–6·7) in the TG4010 group and 5·1 months (4·2–5·9) in the placebo group (HR 0·74 [95% CI 0·55–0·98]; one-sided p=0·019). In patients with TrPAL values of less than or equal to the ULN, the HR for progression-free survival was 0·75 (0·54–1·03); the posterior probability of the HR being less than 1 was 98·4%, and thus the primary endpoint was met. In patients with TrPAL values of greater than the ULN, the HR for progression-free survival was 0·77 (0·42–1·40); the posterior probability of the HR being greater than 1 was 31·3%, and the primary endpoint was not met. We noted grade 1–2 injection-site reactions in 36 (33%) of 110 patients in the TG4010 group versus four (4%) of 107 patients in the placebo group. We noted no grade 3 or 4 nor serious adverse events deemed to be related to TG4010 only. Four (4%) patients presented grade 3 or 4 adverse events related to TG4010 and other study treatments (chemotherapy or bevacizumab) versus 11 (10%) in the placebo group. No serious adverse event was related to the combination of TG4010 with other study treatments. The most frequent severe adverse events were neutropenia (grade 3 29 [26%], grade 4 13 [12%] in the TG4010 group vs grade 3 22 [21%], grade 4 11 [10%] in the placebo group), anaemia (grade 3 12 [11%] vs grade 3 16 [15%]), and fatigue (grade 3 12 [11%], grade 5 one [1%] vs grade 3 13 [12%]; no grade 4 events). TG4010 plus chemotherapy seems to improve progression-free survival relative to placebo plus chemotherapy. These data support the clinical value of the TrPAL biomarker in this clinical setting; because the primary endpoint was met, the trial is to continue into the phase 3 part. Transgene, Avancées Diagnostiques pour de Nouvelles Approches Thérapeutiques (ADNA), and OSEO.

The objective of this study was to evaluate whether interleukin-2 (IL-2) receptor expression on CD56(bright) natural killer (NK) cells predicted CD56(bright) NK cell expansion and therapeutic response to daclizumab (DAC) in multiple sclerosis (MS). DAC exposure, CD56(bright) NK cell counts, IL-2 receptor alpha (CD25) and beta (CD122) subunits, and new or enlarged lesions on brain MRI were measured in 64 subjects in a pharmacokinetic/pharmacodynamic substudy of the phase 2 CHOICE trial at multiple time points. Peripheral blood mononuclear cell (PBMC) samples were obtained from healthy subjects to assess the relationship among DAC treatment, intermediate affinity IL-2 signaling, and CD56(bright) NK cell expansion. Increased CD56(bright) NK cell counts in DAC/interferon beta (IFNβ)-treated subjects were observed by day 14, the first post-dosing time point (mean [SD] ln{CD56(bright) NK cell count}: DAC high/IFNβ, 2.01 [1.25]; DAC low/IFNβ, 2.29 [1.06]; placebo/IFNβ, 1.01 [1.03]; adjusted p = 0.003), and persisted throughout the treatment period. Higher DAC dose predicted a faster rate of CD56(bright) NK cell expansion (p < 0.001), but individual subjects' increases in CD56(bright) NK cells from baseline levels were only weakly correlated with DAC exposure (r(2) = 0.167). Higher expression of the intermediate-affinity IL-2 receptor subunit (CD122) on CD56(bright) NK cells at baseline predicted fewer new gadolinium-enhanced (Gd+) lesions during the treatment period (1.77 vs. 0.62 adjusted mean new Gd+ lesions during weeks 8-24, lowest vs. highest quartile of percentage CD122(+) CD56(bright) NK cells; p = 0.033) and a greater increase in CD56(bright) NK cell counts at the end of DAC dosing (p = 0.029). CD56(bright) NK cell expansion after DAC treatment appears to reflect individual differences in the capacity for intermediate-affinity IL-2 signaling and could provide a basis for predicting clinical response to DAC in MS.

Natural killer (NK) cells have an important function in the anti-tumor response early after stem cell transplantation (SCT). As part of a prospective randomized phase III study, directly comparing the use of CD3 + /CD19 + -depleted peripheral blood stem cell (PBSC) harvests with CD34 + -selected PBSC harvests in allogeneic human leukocyte antigen-matched SCT, we here show that the use of CD3 + /CD19 + -depleted PBSC grafts leads to early NK cell repopulation and reconstitution of the CD56 dim and CD56 bright NK cell subsets, with concomitant high cytolytic capacity. In the CD34 group, this process took significantly longer. Moreover, in the CD3/19 group after reconstitution, a higher percentage of killer immunoglobulin-like receptor-positive NK cells was found. Although similar percentages of CD94-positive NK cells were found in both groups, in the CD34 group, almost all expressed the inhibitory CD94:NKG2A complex, whereas in the CD3/19 group, the inhibitory CD94:NKG2A and the activating CD94:NKG2C complex were equally distributed. This preferential development of NKG2C-expressing NK cells in the CD3/19 group was paralleled by a loss of NKG2A-mediated inhibition of NK cell degranulation. These results show that the use of CD3 + /CD19 + -depleted grafts facilitates strong NK cell cytolytic responses directly after SCT, and the rapid emergence of an NK cell receptor phenotype that is more prone to activation.

Innate lymphoid cells are cytokine-producing cells that contribute to tissue homeostasis. Spits and colleagues identify a human innate cell population that expresses T-bet and IFN-γ and is prevalent in Crohn's disease. Innate lymphoid cells (ILCs) are effectors of innate immunity and regulators of tissue modeling. Recently identified ILC populations have a cytokine expression pattern that resembles that of the helper T cell subsets T H 2, T H 17 and T H 22. Here we describe a distinct ILC subset similar to T H 1 cells, which we call 'ILC1'. ILC1 cells expressed the transcription factor T-bet and responded to interleukin 12 (IL-12) by producing interferon-γ (IFN-γ). ILC1 cells were distinct from natural killer (NK) cells as they lacked perforin, granzyme B and the NK cell markers CD56, CD16 and CD94, and could develop from RORγt + ILC3 under the influence of IL-12. The frequency of the ILC1 subset was much higher in inflamed intestine of people with Crohn's disease, which indicated a role for these IFN-γ-producing ILC1 cells in the pathogenesis of gut mucosal inflammation.

Alzheimer’s disease (AD) is the most common dementia without an effective cure at least partially due to incomplete understanding of the disease. Inflammation has emerged as a central player in the onset and progression of AD. As innate lymphoid cells, natural killer (NK) cells orchestrate the initiation and evolution of inflammatory responses. Yet, the transcriptomic features of NK cells in AD remain poorly understood. We assessed the diversity of NK cells using web-based single-cell RNA sequencing data of blood NK cells from patients with AD and control subjects and flow cytometry. We identified a contraction of NK cell compartment in AD, accompanied by a reduction of cytotoxicity. Unbiased clustering revealed four subsets of NK cells in AD, i.e., CD56 bright NK cells, CD56 dim effector NK cells, adaptive NK cells, and a unique NK cell subset that is expanded and characterized by upregulation of CX3CR1, TBX21, MYOM2, DUSP1, and ZFP36L2, and negatively correlated with cognitive function in AD patients. Pseudo-temporal analysis revealed that this unique NK cell subset was at a late stage of NK cell development and enriched with transcription factors TBX21, NFATC2, and SMAD3. Together, our study identified a distinct NK cell subset and its potential involvement in AD.

Background A follicular thyroid tumour called Non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) poses crossing-over morphologic characteristics with more thyroid follicular lesions whether benign or cancerous nodules. This study focuses on analysing the expression of CD56, HBME-1, RRM2 and APLP2 IHC markers in NIFTP versus other thyroid follicular lesions and their diagnostic validity was also evaluated. Methods one hundred and nine thyroidectomy specimens including 31 NIFTP, 34 non-neoplastic, 34 papillary thyroid carcinoma (PTC) and 10 invasive encapsulated follicular variant papillary thyroid carcinoma (IEFVPTC) cases, were acquired between 2019 and 2022 from the Menoufia University’s Faculty of Medicine’s Pathology Department. Tissue microarray construction (TMA) blocks were prepared and CD56, HBME-1, RRM2 and APLP2 immunostaining were performed. Results For CD56, 64.5% of NIFTP, 97.1% of the non-neoplastic group and 0% of both PTC and IEFVPTC were positive. For HBME-1, 61.3% of NIFTP, 0% of non-neoplastic, 100% of PTC and 100% of IEFVPTC were positive. For RRM2, all cases of NIFTP and the non-neoplastic group were negative, 88.2% of PTC and 100.0% of IEFVPTC were positive. For APLP2, 90.3% of NIFTP, 100% of the non-neoplastic group, 100% of PTC and 100% of IEFVPTC were positive. In differentiating NIFTP from non-neoplastic cases, the most sensitive marker was CD56 at H-score < 225 (sensitivity 95%) and the most specific was HBME-1 (specificity 100%). In various combinations, the panel of combined HBME-1 with either CD56 or APLP-2 improves their specificity (96.67% and 100% respectively) and the diagnostic accuracy (86.79 and 83.87, respectively) and therefore, combined HBME-1 and CD56 seems to be the most significant than using a single marker. In differentiation between NIFTP and PTC/IEFVPTC, the most sensitive marker was RRM2 (100% sensitivity for both groups) with the highest diagnostic accuracy (93.85% and 100%, respectively) and the most specific was CD56 (specificity 100% for both groups). Conclusions Immunohistochemical markers such as CD56, HBME-1, RRM2, and APLP2 may aid in the diagnosis of NIFTP and its distinction from other follicular lesions.

Tendon injury occurs at high frequency and is difficult to repair. Identification of human stem cells being able to regenerate tendon will greatly facilitate the development of regenerative medicine for tendon injury. Genetic and functional analyses identify human CD29+/CD56+ myogenic progenitors with tenogenic differentiation potential in vitro and in vivo. Transplantation of human CD29+/CD56+ myogenic progenitors contributes to injured tendon repair and thus improves locomotor function. Interestingly, the tendon differentiation potential in mouse muscle stem cells is minimal and the higher TGFβ signaling level may be the key for the distinct feature of human CD29+/CD56+ myogenic progenitors. The discovery of bi-potential CD29+/CD56+ myogenic progenitors highlights their potential as a novel adult stem cell source for tendon regeneration.

Natural killer (NK) cells are lymphocytes of the native immune system that play a pivotal role in host defense and immune surveillance. While the conceptual view of NK-neoplasms is evolving, little is known about the rare NK lymphoblastic leukemia (NK-LL), which remains as a provisional entity in the 2016 WHO Classification. The goal of this study is to characterize NK-LL cases and compare with other CD56 co-expressing acute leukemias. We identified 105 cases, diagnosed as NK-LL (6), CD56+ acute undifferentiated leukemia (AUL) (6), CD56+ T-lymphoblastic leukemia (T-LL) (51), and CD56+ acute myeloid leukemia (AML) (42). Compared to AUL patients, NK-LL patients were significantly younger (p = 0.021) and presented with higher white blood cell (WBC) (p = 0.037) and platelet counts (p = 0.041). Flow cytometry showed more frequent expression of cytoplasmic CD3 (cCD3, p = 0.064) and CD33, (p = 0.065), while HLA-DR was significantly absent from NK-LL (p = 0.035) compared to AUL. Compared to T-ALL, NK-LL cases showed less frequent cCD3 (p = 0.002), CD4 (p = 0.051), and CD10 expression (p = 0.06). The frequency of abnormal karyotypes was similar between NK-LL, AUL, and T-ALL. The mutational profile differed in four leukemia groups, with a significance enrichment of NOTCH1 (p = 0.002), ETV6 (p = 0.002) and JAK3 (p = 0.02) mutations in NK-LL as compared to AML. As compared to T-ALL, NK-LL cases showed a higher number of total mutations (p = 0.04) and significantly more frequent ETV6 mutations (p = 0.004). Clinical outcome data showed differences in overall survival between all four groups (p = 0.0175), but no difference in event free survival (p = 0.246). In this largest study to date, we find that that NK-LL shows clinical presentation, immunophenotypic and molecular characteristics distinct from AUL, T-ALL, and AML. Our findings suggest NK-LL is a distinct acute leukemia entity and should be considered in the clinical diagnosis of acute leukemias of ambiguous lineage.

NK-22 cells: an anti-inflammatory role A previously unrecognized subset of human natural killer (NK) lymphocytes is reported. These 'NK-22' cells are selectively localized in tonsil and gut mucosa and, in contrast to conventional NK cells, are poorly cytotoxic and secrete little or no interferon. Rather, they specialize in the secretion of interleukin 22 (IL-22), IL-26 and leukaemia inhibitory factor, all of which have been implicated in the protection of epithelia. The properties of NK-22 cells are consistent with an anti-inflammatory response that may contribute to the maintenance of mucosal integrity. This study identifies a subset of natural killer (NK) cells in the gut that produce interleukin-22, rather than mediate target cell killing. It is suggested that these NK cells, referred to as NK-22 cells, may help constrain inflammation and contribute to the maintenance of mucosal integrity. Natural killer (NK) cells are classically viewed as lymphocytes that provide innate surveillance against virally infected cells and tumour cells through the release of cytolytic mediators and interferon (IFN)-γ. In humans, blood CD56 dim NK cells specialize in the lysis of cell targets 1 . In the lymph nodes, CD56 bright NK cells secrete IFN-γ cooperating with dendritic cells and T cells in the generation of adaptive responses 1 , 2 . Here we report the characterization of a human NK cell subset located in mucosa-associated lymphoid tissues, such as tonsils and Peyer’s patches, which is hard-wired to secrete interleukin (IL)-22, IL-26 and leukaemia inhibitory factor. These NK cells, which we refer to as NK-22 cells, are triggered by acute exposure to IL-23. In vitro , NK-22-secreted cytokines stimulate epithelial cells to secrete IL-10, proliferate and express a variety of mitogenic and anti-apoptotic molecules. NK-22 cells are also found in mouse mucosa-associated lymphoid tissues and appear in the small intestine lamina propria during bacterial infection, suggesting that NK-22 cells provide an innate source of IL-22 that may help constrain inflammation and protect mucosal sites.

Endoscopic ultrasound-guided fine-needle aspiration has become the common procedure for the diagnosis of pancreatic mass, and cytological examination is usually the first approach. Solid pseudopapillary neoplasm (SPN) cytologically represents papillary structures of branching capillaries surrounded by discohesive neoplastic cells. However, it may present various degrees of tissue degeneration, causing diagnostic challenges. Here, we report a 21-year-old female who had a 2-cm-sized mass in the pancreas head. Cytological examination revealed clumps of small round/oval cells that represented microcystic configurations with mucus, mimicking adenoid cystic carcinoma or mucinous adenocarcinoma. Cercariform cells, nuclear grooves/folding, and cytoplasmic vacuoles were not observed. Histopathological examination revealed confluent small glandular structures containing acidic mucus. The tumor cells were positively stained for β-catenin, CD10, and CD56, and negative for chromogranin A and E-cadherin, suggesting SPN, micropseudocystic variant. This variant has been scarcely described, but we should recognize it for accurate cytological triage of pancreatic tumors.