Chimeric antigen receptor T-cell (CAR T) therapy development represents a promising therapeutic strategy for HER2-positive non-small cell lung cancer (NSCLC), a subtype accounting for 1-5% of NSCLC cases. However, the clinical efficacy of CAR T cells remains limited by poor tumor infiltration. Here, we identify NSCLC-specific overexpression of the CXCL13 and CCL20 chemokines within the tumor microenvironment (TME) and develop a dual chemokine receptor strategy to overcome this barrier.
Western blotting and qRT-PCR were used to quantify chemokine receptor expression (CXCR5, CCR6) in NSCLC. Cytotoxicity and antigen recognition sensitivity of CXCR5-CCR6-HER2-CAR T cells against target cells were assessed using in vitro co-culture assays. In vitro proliferation and migration capacities of these engineered T cells were also evaluated. Anti-tumor activity was determined through in vivo animal experiments.
We demonstrate for the first time that HER2-targeted CAR T cells co-expressing the chemokine receptors CXCR5 and CCR6 selectively respond to CXCL13 and CCL20, which are highly expressed in the NSCLC TME. This dual chemokine receptor co-expression strategy has not been previously applied to solid tumors. The CXCR5/CCR6 pairing synergistically enhanced the antitumor activity of HER2-CAR T cells in both in vitro and in vivo models. Furthermore, CXCR5 and CCR6 co-expression significantly improved the in vitro cytotoxicity, antigen recognition sensitivity, proliferation, and migration of HER2-CAR T cells. In vivo, this modification enhanced HER2-CAR T cell survival, expansion, and tumor infiltration.
CXCR5/CCR6 co-expression establishes a novel therapeutic paradigm for refractory HER2-positive NSCLC. Its modular design facilitates rapid clinical translation and adaptation to other chemokine-defined solid tumors.
© 2025. The Author(s).

Thymoma is often associated with myasthenia gravis (MG). Abnormal lymphocyte differentiation often occurs in the thymoma tumor microenvironment (TME), leading to thymoma-associated autoimmune diseases. Thymoma is closely related to MG, although the underlying mechanisms remain unclear. Patients diagnosed with thymoma were selected and divided into three groups on the basis of MG diagnosis and severity: thymoma alone (T), thymoma-associated MG with mild and moderate clinical symptoms (T + MGL), and severe thymoma-associated MG (T + MGH). Tumor tissue and peripheral blood samples were collected from each group of patients. In the thymoma TME, CD19+ B cells, CD19+CD5+CD1d+ regulatory B cells (Bregs), CD4+ T cells, and CD4+CXCR5+ T follicular helper cells (Tfhs) were localized via multilabel immunofluorescence staining to clarify the relationship between local immune infiltration in the TME and MG severity. Bregs, Tfhs, and other immune cells in the peripheral blood were assessed by flow cytometry. B-cell-enriched regions were detected around blood vessels in the thymoma TME. Breg infiltration in the TME decreased with MG aggravation, whereas the opposite trend was observed for Tfh cells. The Breg/Tfh ratios in the peripheral blood and TME were broadly consistent, and the levels of both types of cells were significantly lower in patients with aggravated MG. Our findings revealed a balance among the Breg/Tfh ratio, immune hyperactivity, and immune tolerance in thymoma-associated MG in both the peripheral blood and the TME. These observations provide new perspectives regarding disease pathogenesis and immunotherapy.
© 2025. The Author(s).

FMS-related tyrosine kinase 3 ligand (FLT3L), encoded by FLT3LG, is a hematopoietic factor essential for the development of natural killer (NK) cells, B cells, and dendritic cells (DCs) in mice. We describe three humans homozygous for a loss-of-function FLT3LG variant with a history of various recurrent infections, including severe cutaneous warts. The patients' bone marrow (BM) was hypoplastic, with low levels of hematopoietic progenitors, particularly myeloid and B cell precursors. Counts of B cells, monocytes, and DCs were low in the patients' blood, whereas the other blood subsets, including NK cells, were affected only moderately, if at all. The patients had normal counts of Langerhans cells (LCs) and dermal macrophages in the skin but lacked dermal DCs. Thus, FLT3L is required for B cell and DC development in mice and humans. However, unlike its murine counterpart, human FLT3L is required for the development of monocytes but not NK cells.
Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.

Currently, the precise causes of over 40 % of recurrent spontaneous abortion (RSA) cases cannot be identified, leading to the term "unexplained RSA" (URSA). Through an exploration of the gut microbiota, metabolites, and immune cell subsets in URSA, this study establishes a link between gut microbiota-derived metabolites and immune cells. The results indicate reduced diversity in the gut microbiota of URSA. Targeted metabolomic analyses reveal decreased levels of gut microbiota-derived deoxycholic acid (DCA), glycolithocholic acid (GLCA), acetate, propionate, and butyrate in URSA. Furthermore, elevated frequencies of Th1, Th17, and plasma B cells, along with decreased frequencies of Tregs and Bregs, are observed in the peripheral blood of URSA. The results demonstrate correlations between the levels of gut microbiota-derived bile acids and short-chain fatty acids and the frequencies of various immune cell subsets in circulation. Collectively, this study uncovers an association between gut microbiota-derived metabolites and circulating immune cell subsets in URSA.
© 2024 The Authors.

Neuromyelitis optica spectrum disorders (NMOSD) are inflammatory autoimmune disorders of the CNS. IgG autoantibodies targeting the aquaporin-4 water channel (AQP4-IgGs) are the pathogenic effector of NMOSD. Dysregulated T follicular helper (Tfh) cells have been implicated in loss of B cell tolerance in autoimmune diseases. The contribution of Tfh cells to disease activity and therapeutic potential of targeting these cells in NMOSD remain unclear. Here, we established an autoimmune model of NMOSD by immunizing mice against AQP4 via in vivo electroporation. After AQP4 immunization, mice displayed AQP4 autoantibodies in blood circulation, blood-brain barrier disruption, and IgG infiltration in spinal cord parenchyma. Moreover, AQP4 immunization induced motor impairments and NMOSD-like pathologies, including astrocytopathy, demyelination, axonal loss, and microglia activation. These were associated with increased splenic Tfh, Th1, and Th17 cells; memory B cells; and plasma cells. Aqp4-deficient mice did not display motor impairments and NMOSD-like pathologies after AQP4 immunization. Importantly, abrogating ICOS/ICOS-L signaling using anti-ICOS-L antibody depleted Tfh cells and suppressed the response of Th1 and Th17 cells, memory B cells, and plasma cells in AQP4-immunized mice. These findings were associated with ameliorated motor impairments and spinal cord pathologies. This study suggests a role of Tfh cells in the pathophysiology of NMOSD in a mouse model with AQP4 autoimmunity and provides an animal model for investigating the immunological mechanisms underlying AQP4 autoimmunity and developing therapeutic interventions targeting autoimmune reactions in NMOSD.