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CD4+ T cells have been well-regarded as ¡°helper¡± cells in activating the cytotoxicity of CD8+ T cells for effective tumor eradication, while few studies have focused on whether CD8+ T cells regulate CD4+ T cells. Our previous studies provided evidence for an interaction between CD4+ and CD8+ T cells after cryo-thermal therapy, but the mechanism remains unclear, especially pertaining to how CD8+ T cells promote the Th1 differentiation of CD4+ T cells. This study revealed that activated CD4+ and CD8+ T cells are critical for CTT-induced antitumor immunity, and the interaction between activated T cells is enhanced. The reciprocal regulation of activated CD8+ and CD4+ T cells was through LFA-1/ICAM-1 interactions, in which CD8+ T cells facilitate Notch1-dependent CD4+ Th1-dominant differentiation and promote IL-2 secretion of CD4+ T cells. Meanwhile, IL-2 derived from CD4+ T cells enhances the cytotoxicity of CD8+ T cells and establishes a positive feedback loop via increasing the expression of LFA-1 and ICAM-1 on T cells. Clinical analyses further validated that LFA-1/ICAM interactions between CD4+ and CD8+ T cells are correlated with clinical outcomes. Our study extends the functions of the LFA-1/ICAM-1 adhesion pathway, indicating its novel role in the interaction of CD4+ and CD8+ T cells.

SummaryAerobic exercise training (AET) has emerged as a strategy to reduce cancer mortality, however, the mechanisms explaining AET on tumor development remain unclear. Tumors escape immune detection by generating immunosuppressive microenvironments and impaired T cell function, which is associated with T cell mitochondrial loss. AET improves mitochondrial content and function, thus we tested whether AET would modulate mitochondrial metabolism in tumor-infiltrating lymphocytes (TIL). Balb/c mice were subjected to a treadmill AET protocol prior to CT26 colon carcinoma cells injection and until tumor harvest. Tissue hypoxia, TIL infiltration and effector function, and mitochondrial content, morphology and function were evaluated. AET reduced tumor growth, improved survival, and decreased tumor hypoxia. An increased CD8+ TIL infiltration, IFN-¦Ã and ATP production promoted by AET was correlated with reduced mitochondrial loss in these cells. Collectively, AET decreases tumor growth partially by increasing CD8+ TIL effector function through an improvement in their mitochondrial content and function. Graphical abstract Highlights?Exercise training reduces tumor growth and improves survival in colorectal cancer?Trained mice present tumors with less hypoxia and higher CD8+ T cells infiltration?The production of IFN¦Ã by CD8+ TIL is increased in exercise-trained mice?CD8+ TIL from trained mice show higher mitochondrial density and function Natural sciences; Biological sciences; Biochemistry; Physiology; Immunology; Systems biology; Cancer systems biology

SummaryMesenchymal stromal cells (MSCs) have been modified via genetic or pharmacological engineering into potent antigen-presenting cells-like capable of priming responding CD8 T cells. In this study, our screening of a variant library of Accum molecule revealed a molecule (A1) capable of eliciting antigen cross-presentation properties in MSCs. A1-reprogrammed MSCs (ARM) exhibited improved soluble antigen uptake and processing. Our comprehensive analysis, encompassing cross-presentation assays and molecular profiling, among other cellular investigations, elucidated A1¡¯s impact on endosomal escape, reactive oxygen species production, and cytokine secretion. By evaluating ARM-based cellular vaccine in mouse models of lymphoma and melanoma, we observe significant therapeutic potency, particularly in allogeneic setting and in combination with anti-PD-1 immune checkpoint inhibitor. Overall, this study introduces a strong target for developing an antigen-adaptable vaccination platform, capable of synergizing with immune checkpoint blockers to trigger tumor regression, supporting further investigation of ARMs as an effective and versatile anti-cancer vaccine. Graphical abstract Highlights?Treatment with A1/antigen mix reprograms MSCs into antigen-presenting cells?The antigen cross-presenting ability of ARM cells require ROS and UPR?ARMs synergize with immune-checkpoint inhibitors in priming potent antitumoral activity Classification Description: Immunology; Pharmaceutical engineering; Cancer