The MITO-END3 trial compared carboplatin and paclitaxel (CP) with avelumab plus carboplatin and paclitaxel (CPA) as first-line treatment in endometrial cancer (EC) patients and demonstrated a significant interaction between avelumab response and mismatch repair status. To investigate prognostic/predictive biomarker, 29 MITO-END3-EC patients were evaluated at pretreatment (B1) and at the end of CP/CPA treatment (B2) for peripheral myeloid-derived suppressor cells (MDSC) and Tregs. At B2, effector Tregs frequency was significantly higher in patients treated with CPA as compared to CP (p = 0.038). Both treatments (CP/CPA) induced significant decrease in peripheral M-MDSC (- 5.41%) in TCGA 2-MSI-high as compared to TCGA-category 4 tumors (p = 0.004). In accordance, both treatments induced M-MDSCs (+ 5.34%) in MSS patients as compared to MSI-high patients (p = 0.001). Moreover, in a subgroup of patients, primary tumors were highly infiltrated by M-MDSCs in MSS as compared to MSI-high ECs. A post hoc analysis displayed higher frequency of M-MDSCs (p = 0.020) and lower frequency of CD4+ (p < 0.005) at pretreatment in EC patients as compared to healthy donors. In conclusion, the peripheral evaluation of MDSCs and Tregs correlated with molecular features in EC treated with CP/CPA and may add insights in identifying EC patients responder to first-line chemo/chemo-immunotherapy.
© 2025. The Author(s).

Chronic myelomonocytic leukaemia (CMML) is a haematological malignancy characterised by overlapping myeloid dysplasia and proliferation with persisting monocytosis. While monocytes are the cardinal malignant cell type in CMML, as a stem cell neoplasm the disease clone comprises most lineages and differentiation stages, including granulocytes. To investigate the pathogenic contribution of granulocytes in CMML maintenance and progression, we performed phenotypic, transcriptomic and functional characterization of CMML granulocytes. Compared with healthy age-matched controls, CMML granulocytes exhibit defective maturation with reduced granularity and phagocytic capacity. Transcriptome analysis revealed activation of pathways linked to proliferation, Myc activity and inflammation. Notably, RETN , which encodes the inflammatory mediator resistin, was upregulated approximately 100-fold in CMML granulocytes; but not differentially expressed in CMML PBMNCs, sorted monocytes, or stem and progenitor cells compared to their healthy counterparts. Accordingly, resistin protein levels were 10-fold higher in plasma from CMML patients and higher plasma resistin levels correlate with poor overall survival and AML-free survival. Remarkably, exposure of healthy monocytes to exogenous recombinant resistin inhibited monocyte maturation and macrophage differentiation. Transcriptome analysis of resistin treated monocytes revealed that resistin induces gene signatures related to immune suppression and myeloid-derived suppressor cell phenotype. We found SEMA4A to be a downstream target of resistin and overexpressed in CMML monocytes. Consistent with known roles for SEMA4A, CMML patients displayed higher percentage of Tregs and elevated Th2/Th1 ratio compared with healthy controls and percentage of Tregs corresponding with associated resistin levels. Furthermore, we demonstrated that resistin directly skews the Th2/Th1 ratio via binding to monocytes. In conclusion, we showed that immature granulocytes in CMML produce high levels of resistin, which contributes to defective monocyte maturation and immune suppression.

Diarrhoea and preweaning mortality in piglets are crucial factors impacting the economic sustainability of the swine industry. Pathogenic infections are among the main causes of diarrhea and mortality. Group 3 innate lymphoid cells (ILC3s) are crucial for safeguarding against pathogenic infections. However, knowledge regarding the development and function of ILC3s in suckling piglets is currently limited. Our findings demonstrate that the development of ILC3s in suckling piglets gradually progresses from day 1 to day 21, with a notable increase observed on day 28. Additionally, the development of NKp46+ILC3s and the production of interleukin (IL)-17A by ILC3s displayed consistent patterns with the changes observed in ILC3s. Notably, interferon (IFN)-γ levels significantly increased on day 14. Moreover, the production of IFN-γ by NKp46+ILC3s was greater than that by NKp46-ILC3s. Importantly, when piglets were subjected to a 4-h challenge with enterotoxigenic Escherichia coli, both the percentages of ILC3s significantly increased, accompanied by increased IL-22 production, highlighting their importance in maintaining intestinal health. The outcomes of this study provide valuable insights for future related research.
© 2024. The Author(s).

Myelofibrosis, which includes primary myelofibrosis (PMF) and secondary myelofibrosis (SMF), can exhibit cytopenic features associated with poor outcomes; however, the underlying mechanisms are unclear. Moreover, characterized by its aggressive nature and limited therapeutic options, myelofibrosis poses a major clinical challenge in hematology. Therefore, in this study, we aimed to identify genetic and immunologic features associated with thrombocytopenia progression and poor prognosis.
The study involved 226 patients with PMF or SMF, who were categorized into three groups: platelet count ≥ 100 × 109/L (PLT ≥ 100 group; n = 131), progression to thrombocytopenia (PROG group; n = 64), and platelet count < 100 × 109/L (PLT < 100 group; n = 31).
Survival analysis revealed 4-year overall survival rate of 57.7%, 89.4%, and 93.9% for the PLT < 100, PROG, and PLT ≥ 100 groups, respectively. Time-dependent covariate analysis of the PLT ≥ 100 and PROG groups revealed inferior overall survival rate of the PROG group. Multivariate analysis indicated that progression to thrombocytopenia and ASXL1 and IDH1 mutations were associated with poor overall survival. Flow cytometry revealed fewer CD45RA+CD4+ T cells in the PROG group than in the PLT ≥ 100 group. ASXL1 mutations were more prevalent in the PROG group than in the other groups, correlating with a reduced number of CD45RA+CD4+ T cells.
ASXL1 mutation and low CD45RA+CD4+ T-cell counts correlated with progression to thrombocytopenia. Our findings underscore the clinical significance of thrombocytopenia dynamics in MF progression and prognosis, with implications for patient management and therapeutic interventions.
Copyright © 2024 Kim, Eom, Lee, Lee, Kim and Lee.

HIV infection significantly affects the frequencies and functions of immunoregulatory CD3+CD4-CD8- double-negative (DN) T-cells, while the effect of early antiretroviral therapy (ART) initiation on these cells remains understudied. DN T-cell subsets were analyzed prospectively in 10 HIV+ individuals during acute infection and following early ART initiation compared to 20 HIV-uninfected controls. In this study, 21 Rhesus macaques (RMs) were SIV-infected, of which 13 were assessed during acute infection and 8 following ART initiation four days post-infection. DN T-cells and FoxP3+ DN Treg frequencies increased during acute HIV infection, which was not restored by ART. The expression of activation (HLA-DR/CD38), immune checkpoints (PD-1/CTLA-4), and senescence (CD28-CD57+) markers by DN T-cells and DN Tregs increased during acute infection and was not normalized by ART. In SIV-infected RMs, DN T-cells remained unchanged despite infection or ART, whereas DN Treg frequencies increased during acute SIV infection and were not restored by ART. Finally, frequencies of CD39+ DN Tregs increased during acute HIV and SIV infections and remained elevated despite ART. Altogether, acute HIV/SIV infections significantly changed DN T-cell and DN Treg frequencies and altered their immune phenotype, while these changes were not fully normalized by early ART, suggesting persistent HIV/SIV-induced immune dysregulation despite early ART initiation.