Small cell lung cancer (SCLC) is difficult to treat due to its aggressiveness, early metastasis, and rapid development of resistance to chemotherapeutic agents. Here, we show that treatment with a dopamine D2 receptor (D2R) agonist reduces tumour angiogenesis in multiple in vivo xenograft models of human SCLC, thereby reducing SCLC progression. An FDA-approved D2R agonist, cabergoline, also sensitized chemotherapy-resistant SCLC tumours to cisplatin and etoposide in patient-derived xenograft models of acquired chemoresistance in mice. Ex vivo, D2R agonist treatment decreased tumour angiogenesis through increased apoptosis of tumour-associated endothelial cells, creating a less favourable tumour microenvironment that limited cancer cell proliferation. In paired SCLC patient-derived specimens, D2R was expressed by tumour-associated endothelial cells obtained before treatment, but D2R was downregulated in SCLC tumours that had acquired chemoresistance. D2R agonist treatment of chemotherapy-resistant specimens restored expression of D2R. Activation of dopamine signalling is thus a new strategy for inhibiting angiogenesis in SCLC and potentially for combatting chemotherapy-refractory SCLC progression.
© 2025. The Author(s).

Despite their clinical success, chimeric antigen receptor (CAR)-T cell therapies for B cell malignancies are limited by lengthy, costly and labor-intensive ex vivo manufacturing procedures that might lead to cell products with heterogeneous composition. Here we describe an implantable Multifunctional Alginate Scaffold for T Cell Engineering and Release (MASTER) that streamlines in vivo CAR-T cell manufacturing and reduces processing time to a single day. When seeded with human peripheral blood mononuclear cells and CD19-encoding retroviral particles, MASTER provides the appropriate interface for viral vector-mediated gene transfer and, after subcutaneous implantation, mediates the release of functional CAR-T cells in mice. We further demonstrate that in vivo-generated CAR-T cells enter the bloodstream and control distal tumor growth in a mouse xenograft model of lymphoma, showing greater persistence than conventional CAR-T cells. MASTER promises to transform CAR-T cell therapy by fast-tracking manufacture and potentially reducing the complexity and resources needed for provision of this type of therapy.
© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.

Chimeric antigen receptor T (CAR-T) cell therapy has produced impressive clinical responses in patients with B-cell malignancies. Critical to the success of CAR-T cell therapies is the achievement of robust gene transfer into T cells mediated by viral vectors such as gamma-retroviral vectors. However, current methodologies of retroviral gene transfer rely on spinoculation and the use of retronectin, which may limit the implementation of cost-effective CAR-T cell therapies. Herein, a low-cost, tunable, macroporous, alginate scaffold that transduces T cells with retroviral vectors under static condition is described. CAR-T cells produced by macroporous scaffold-mediated viral transduction exhibit >60% CAR expression, retain effector phenotype, expand to clinically relevant cell numbers, and eradicate CD19+ lymphoma in vivo. Efficient transduction is dependent on scaffold macroporosity. Taken together, the data show that macroporous alginate scaffolds serve as an attractive alternative to current transduction protocols and have high potential for clinical translation to genetically modify T cells for adoptive cellular therapy.
© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

A significant proportion of cancer patients do not respond to immune checkpoint blockade. To better understand the molecular mechanisms underlying these treatments, we explored the role of CD4+Foxp3- T cells expressing PD-1 (4PD1hi) and observed that 4PD1hi accumulate intratumorally as a function of tumor burden. Interestingly, CTLA-4 blockade promotes intratumoral and peripheral 4PD1hi increases in a dose-dependent manner, while combination with PD-1 blockade mitigates this effect and improves anti-tumor activity. We found that lack of effective 4PD1hi reduction after anti-PD-1 correlates with poor prognosis. Mechanistically, we provide evidence that mouse and human circulating and intra-tumor 4PD1hi inhibit T cell functions in a PD-1/PD-L1 dependent fashion and resemble follicular helper T cell (TFH)-like cells. Accordingly, anti-CTLA-4 activity is improved in TFH deficient mice.Copyright © 2018 Elsevier Inc. All rights reserved.

T follicular helper (Tfh) cells are known to support effector B cells and enhance autoimmunity; however, the association between the Tfh cells and B cells in ankylosing spondylitis (AS) is unclear. The aim of the present study was to measure the frequency of circulating cluster of differentiation (CD)4+ C-X-C chemokine receptor type 5 (CXCR5)+ Tfh cells and B cell subtypes in peripheral blood from patients with AS, and evaluate the correlation of these factors. Percentages of peripheral blood circulating CD4+CXCR5+ Tfh cells and B cell subtypes were measured via flow cytometry and the disease activity of individual patients was measured using the Bath AS Disease Activity Index (BASDAI). The potential association among these measures was analyzed via Spearman's or Pearson's correlations. In comparison with those in healthy controls (HC), significantly increased percentages of CD4+CXCR5+ cTfh, CD4+CXCR5+ programmed death 1+, CD4+CXCR5+ inducible T cell costimulator (ICOS)+, CD3+CD8-CXCR5+ interleukin (IL)-21+ T cells, CD19+CD27high plasmablast and CD19+CD38+ antibody-secreting B cells were detected in patients with AS, whereas there was no significant difference in CD19+CD27- naïve B cells and CD19+CD27+ memory B cells. When Patients with AS were divided into high and low activity groups, significantly higher percentages of CD4+CXCR5+, CD3+CD8-CXCR5+IL-21+ T cells, CD19+CD27- naïve B cells and CD19+CD38+ antibody-secreting B cells, and lower CD19+CD27+ memory B cells were detected in high activity AS group compared with the low activity AS group. In addition, percentages of CD4+CXCR5+ circulating (c)Tfh, CD3+CD8-CXCR5+IL-21+ T and CD19+CD38+ antibody-secreting B cells were positively correlated with BASDAI values. Furthermore, the percentage of CD4+CXCR5+ cTfh cells was positively correlated with CD19+CD38+ antibody-secreting B cells and the percentage of CD3+CD8-CXCR5+IL-21+ T cells was positively correlated with CD19+CD27- naïve B cells in patients with AS. These findings suggest that CD4+CXCR5+ cTfh, CD3+CD8-CXCR5+IL-21+ T and CD19+CD38+ antibody-secreting B cells may participate in the pathogenesis of AS because of their distinct functions. As such, levels of cTfh and B cell subtypes may be a useful biomarker for the evaluation of disease activity in patients with AS.