Inflammatory arthritis (IA) is characterized by persistent joint inflammation and immune cell infiltration, including CD1c+ dendritic cells (DCs), comprising DC2s and DC3s. To investigate their developmental and functional specialization in IA, we characterized DC2s and DC3s in the peripheral blood (PB) and synovial fluid (SF) of patients with IA. DC3 frequencies were increased in PB of patients with juvenile idiopathic arthritis and correlated with disease activity in early rheumatoid arthritis. While PB DC3s showed strongly impaired T cell activation, SF DC3s induced only marginally lower T cell proliferation compared to DC2s and primed higher frequencies of IL-17+ and IFN γ + T cells. Furthermore, SF from patients with IA induced the DC3 phenotype in DC2s from healthy donors, an effect abrogated by IL-6 receptor blockade and dependent on JAK/STAT3 signaling. Altogether, these findings reveal the impact of tocilizumab and JAK inhibitors on inflammatory DC3s in IA and offer mechanistic insights for IA treatment.
© 2025 The Author(s).

Multiple sclerosis (MS) is a chronic immune-mediated demyelinating disease of the central nervous system, whereby clinical disease activity is primarily monitored by magnetic resonance imaging.
Given the limitations associated with implementing and acquiring novel and emerging imaging biomarkers in routine clinical practice, the discovery of biofluid biomarkers may offer a more simple and cost-effective measure that would improve accessibility, standardization, and patient care. Extracellular vesicles (EVs) are nanoparticles secreted from cells under both homeostatic and pathological states, and have been recently investigated as biomarkers in MS. The objectives of this study were to longitudinally measure levels of specific immune cell-derived EVs in MS and provide evidence that EV sub-populations may serve as biomarkers of disease activity, axonal injury, and/or clinical disability.
Our results demonstrate that the rate of clinical disability in MS negatively correlates with changes in circulating CD3+ EVs within the plasma. Additionally, numbers of CD4+ EVs decrease in individuals with increasing pNfL levels overtime whereby the magnitude of the pNfL increase negatively correlates with changes in plasma CD4+ and CD8+ EVs. Finally, when applying NEDA-3 criteria to define active versus stable disease, individuals with active disease had significantly elevated CD4+ and CD8+ EVs compared to stable disease.
In summary, the analysis of specific immune cell-derived EV subsets may provide a method to monitor disability accumulation, disease activity, and axonal injury in MS, while also providing insights into the pathophysiology and cellular/molecular mechanisms that influence progression.
© The Author(s) 2025. Published by Oxford University Press on behalf of the British Society for Immunology.

While pediatric cancer patients receive intensive chemotherapy, its impact on peripheral T cells and subsequently to disease outcomes are not fully characterized. Here, we assessed T-cell dynamics during treatment, identifying associations with outcomes through immune phenotyping and T-cell Receptor (TCR) sequencing in pediatric solid and hematologic malignancies. We show that while levels of immune checkpoint proteins (PD-1, LAG3, and TIM3) at baseline were highest in lymphomas compared to other cancer groups, they increased significantly in response to therapy in all cancers. Levels of Central Memory (CM) T cells increased in leukemias and solid tumors, while naïve T cells and cell-free TCR diversity decreased in lymphomas. By combining immune cell and TCR repertoire features across all timepoints, we proposed the Dynamic Immunogenomic Score (DIS) to measure patient-specific effects of therapy on the peripheral T-cell population. Higher DIS was associated with high-risk cancer types and logistic regression analysis revealed it may predict incidence of relapse in leukemia patients. TCR specificity analysis revealed patient-specific clonal dynamics and differential detection of virally-associated TCRs in cancer patients compared to healthy individuals. Our results highlight the potential of early upfront immunogenomic profiling in identifying high-risk patients that may be predictive in light of emerging cellular immunotherapies.

Cytotoxic CD8+ T lymphocyte (CTL) recognition of non-mutated tumor-associated antigens (TAA), present on cancer cells and also in healthy tissues, is an important element of cancer immunity, but the mechanism of its selectivity for cancer cells and opportunities for its enhancement remain elusive. In this study, we found that CTL expression of the NK receptors (NKR) DNAM1 and NKG2D was associated with the effector status of CD8+ tumor-infiltrating lymphocytes and long-term survival of patients with melanoma. Using MART1 and NY-ESO-1 as model TAAs, we demonstrated that DNAM1 and NKG2D regulate T-cell receptor (TCR) functional avidity and set the threshold for TCR activation of human TAA-specific CTLs. Superior co-stimulatory effects of DNAM1 over CD28 involved enhanced TCR signaling, CTL killer function, and polyfunctionality. Double transduction of human CTLs with TAA-specific TCR and NKRs resulted in strongly enhanced antigen sensitivity, without a reduction in antigen specificity and selectivity of killer function. In addition, the elevation of NKR ligand expression on cancer cells due to chemotherapy also increased CTL recognition of cancer cells expressing low levels of TAAs. Our data help explain the ability of self-antigens to mediate tumor rejection in the absence of autoimmunity and support the development of dual-targeting adoptive T-cell therapies that use NKRs to enhance the potency and selectivity of recognition of TAA-expressing cancer cells.
©2024 American Association for Cancer Research.

The human dendritic cell (DC) family has recently been expanded by CD1c+CD14+CD163+ DCs, introduced as DC3s. DC3s are found in tumors and peripheral blood of cancer patients. Here, we report elevated frequencies of CD14+ cDC2s, which restore to normal frequencies after tumor resection, in non-small cell lung cancer patients. These CD14+ cDC2s phenotypically resemble DC3s and exhibit increased PD-L1, MERTK, IL-10, and IDO expression, consistent with inferior T cell activation ability compared with CD14- cDC2s. In melanoma patients undergoing CD1c+ DC vaccinations, increased CD1c+CD14+ DC frequencies correlate with reduced survival. We demonstrate conversion of CD5+/-CD1c+CD14- cDC2s to CD14+ cDC2s by tumor-associated factors, whereas monocytes failed to express CD1c under similar conditions. Targeted proteomics identified IL-6 and M-CSF as dominant drivers, and we show that IL-6R and CSF1R inhibition prevents tumor-induced CD14+ cDC2s. Together, this indicates cDC2s as direct pre-cursors of DC3-like CD1c+CD14+ DCs and provides insights into the importance and modulation of CD14+ DC3s in anti-tumor immune responses.
Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.