Cytopenia is one of the most common adverse events following the CAR-T cell infusion, affecting the quality of life and potentially leading to life-threatening bleeding and infection. This study ai...

Acteoside attenuates hydrogen peroxide-induced injury of retinal ganglion cells via the CASC2/miR-155/mTOR axis Xiaoting Xi, Jia Ma, Qianbo Chen, Xuewei Wang, Yuan Xia, Xuewei Wen, Jin Yuan, Yan Li

Chimeric antigen receptor T-cell (CAR-T) therapy targeting B-cell maturation antigen (BCMA) has achieved notable efficacy in relapsed/refractory multiple myeloma (RRMM), yet most patients eventually relapse, highlighting the need to elucidate mechanisms of resistance. In this study, we investigated the role of TIGIT in resistance to BCMA-CAR-T therapy. Tumor-infiltrating T cells from RRMM patients receiving BCMA-CAR-T therapy were analyzed by single-cell RNA sequencing, and immune checkpoint expression was further assessed by flow cytometry. Functional assays, including luciferase-based cytotoxicity, CD107a degranulation, CFSE proliferation, and CD45RO/CD62L phenotyping, were performed to investigate the effects of TIGIT inhibition through knockout or anti-TIGIT monoclonal antibodies (mAbs). In a humanized immune cell-reconstituted mouse model, TIGIT blockade was further evaluated for its effects on tumor growth and T cell exhaustion. T cells from patients with early relapse exhibited higher TIGIT expression than those from patients with durable responses, and elevated TIGIT levels were correlated with increased tumor burden and poor prognosis. While TIGIT blockade exerted limited effects on CAR-T function in vitro, it markedly enhanced CAR-T proliferation, mitigated T cell exhaustion, and improved antitumor efficacy in vivo, particularly when mediated by anti-TIGIT mAbs. Transcriptomic profiling further revealed that TIGIT modulates CAR-T activity by regulating cytokines and chemokines pathways and T cell activation, findings that were preliminarily validated by functional assays. Collectively, these findings identify TIGIT as a critical regulator of resistance to BCMA-CAR-T therapy and highlight TIGIT blockade as a promising strategy to enhance CAR-T efficacy and overcome relapse in multiple myeloma.

Chimeric antigen receptor (CAR)-T therapy has emerged as a promising treatment for hematologic malignancies. However, cytopenia remains one of the most frequent and challenging adverse effects of this therapy. We conducted a retrospective analysis of 26 patients with relapsed/refractory aggressive B-cell lymphoma who received CAR-T therapy at our center. Subsequently, to investigate measures to address cytopenias following CAR-T therapy, we isolated and generated murine CAR-T cells and bone marrow-derived mesenchymal stem cells (MSCs), establishing a murine syngeneic CAR-T therapy model. We assessed the impact of MSC infusion on hematopoietic recovery post-CAR-T therapy by evaluating complete blood count, bone marrow hematopoietic stem cells and their subpopulations, bone marrow histomorphology, and hematopoiesis-related genes. All patients experienced cytopenias to varying degrees, with complete lineage involvement in half of the patients. Grade ≥ 3 cytopenias were observed in 88.46% of the patients. CAR-T therapy was associated with a higher incidence of biphasic, late-onset, or prolonged cytopenias. Survival analysis indicated that neutropenia and lymphopenia tended to be associated with better prognosis, whereas thrombocytopenia tended to be related to poorer outcomes. Through animal experiments, we discovered that MSCs infusion boosted HSCs and their long-term subpopulations, enhancing hematopoietic recovery, particularly in the megakaryocyte lineage, and mitigating bone marrow damage. Importantly, both in vitro and in vivo experiments demonstrated that MSCs did not compromise the activity or antitumor efficacy of CAR-T cells. Our findings propose MSCs infusion as a promising strategy to address cytopenias, particularly thrombocytopenia, after CAR-T therapy. This approach could help overcome certain limitations of cellular immunotherapy by enhancing hematopoietic recovery without compromising the efficacy of CAR-T cells.

The incidence of both prostate cancer (PCa) and metabolic syndrome (MS) has been steadily increasing due to changes in population structure and lifestyle. These two conditions frequently co-occur, yet their shared pathogenic mechanisms remain unclear. In this study, we utilized bioinformatics and machine learning techniques to analyze public datasets and validated our findings using clinical specimens from our center to identify common signature genes between PCa and MS. We began by screening differentially expressed genes (DEGs) and module genes through Linear models for microarray analysis (Limma) and Weighted Gene Co-expression Network Analysis (WGCNA) of four microarray datasets from the GEO database (PCa: GSE8511, GSE32571, and GSE104749; MS: GSE98895). Comprehensively bioinformatics analyses, including functional enrichment, LASSO, and random forest algorithms, coupled with receiver operating characteristic (ROC) and precision recall curve (PRC) analyses were conducted. We identified 423 DEGs in the PCa dataset and 2481 differentially modular genes in the MS dataset. Among these, 52 intersection genes enriched in immunomodulatory pathways were found. Three common signature genes, namely GPD1L, ACY1, and C12orf75, were identified through LASSO and random forest analyses. Subsequent validation using clinical specimens confirmed differential expression of these genes in PCa, with survival analysis indicating that elevated expression of ACY1 is associated with adverse prognosis in PCa patients. Additionally, immunoinfiltration analysis revealed higher levels of macrophage M0 and activated dendritic cells in PCa tissues. In summary, our study identifies three shared signature genes between PCa and MS, with ACY1 demonstrating adverse prognostic significance in PCa. Our findings provide a foundation for elucidating the pathogenic mechanisms and interplay between PCa and MS, offering novel insights for identifying potential therapeutic targets in PCa.