Project description:Here, we report the immune-mediated mechanisms underlying the improved activity of immune checkpoint blockade in glycolysis-defective tumor models.
Project description:Here, we report the immune-mediated mechanisms underlying the improved activity of immune checkpoint blockade in glycolysis-defective tumor models.
Project description:Coinhibitory receptor blockade is a promising strategy to boost immunity against a variety of human cancers. However, many patients still do not benefit from this treatment, and responders often experience immune-related toxicities. These issues highlight the need for improved understanding of checkpoint blockade, but the T cell-intrinsic signaling pathways and gene expression profiles engaged during treatment are not well defined, particularly for combination approaches. We utilized a murine model of CD8+ T cell tolerance to address these issues. We used microarrays to examine the global transcriptional response of T cells rendered tolerant in vivo by encounter with tumor/self-antigen versus T cells activated in response to an immunogenic tumor. RNA isolated from naive Gag-specific T cells was compared to RNA isolated from T-cells transferred into B6 mice with established FBL tumor (immune) and from Alb:Gag mice (tolerant). Two days after T cell transfer, recipient spleen and lymph nodes were harvested and pooled. Transferred cells were then sorted based on CD8+ CD90.1+ CD69hi to a >96% purity using a FACSAria III (BD Biosciences). There were 3 biological replicates per condition.
Project description:The induction of proinflammatory T cells by dendritic cell (DC) subtypes is critical for anti-tumor responses and effective immune checkpoint blockade (ICB) therapy. Here we show that human CD1c+CD5+ dendritic cells are reduced in melanoma-affected lymph nodes, with CD5 expression on DCs correlating with patient survival. Activating CD5 on DCs enhanced T-cell priming and improved survival after immune checkpoint blockade therapy. CD5+ DC numbers increased during ICB treatment, and low IL-6 levels promoted their de novo differentiation. Mechanistically, CD5 expression by DCs was required to generate optimally protective CD5hi T helper and CD8+ T cells; further, deletion of CD5 from T cells dampened tumor elimination in response to ICB therapy in vivo. Thus, CD5+ dendritic cells are an essential component of optimal immune checkpoint blockade therapy.
Project description:To comprehensively characterize the changes within the TME during TREM1 deficiency and anti-PD-1 immune checkpoint blockade therapy, we performed scRNA-seq analysis of the CD45+ TICs in melanoma-bearing C57BL/6 mice receiving the various treatments. We analyzed approximately 8,249 CD45+ cells from the treatment groups with t-SNE analysis, identifying 10 distinct clusters of tumor-infiltrating immune cells
Project description:Immunotherapy has revolutionized cancer treatment over the past decade. However, in most solid tumors, its effectiveness is often impaired owing to immune-resistance mediated through the tumor microenvironment (TME). In fibrotic cancers such as cholangiocarcinoma (CCA), the extracellular matrix (ECM) and cancer-associated fibroblasts (CAFs) create a dense, rigid stroma that hinders immune cell infiltration and fosters immunosuppression. Overcoming these physical and biological barriers is critical to fully unleash the potential of immunotherapeutic approaches. Here, the combination of photothermal therapy (PTT) with gold-iron oxide nanoflowers (GIONFs) effectively reshapes the TME by reducing ECM stiffness and facilitating immune cell infiltration. The GIONF-mediated TME mechanical reprogramming in combination with PD-1 immune checkpoint blockade leads to T-cell activation and reduces the immunosuppressive CAF subset. In preclinical models, this combination approach significantly supported anti-tumor immune responses and improved tumor control. Our findings emphasize the therapeutic potential of reshaping the TME to overcome immunotherapy resistance in fibrotic tumors like CCA. Targeting both the ECM and immune checkpoints may therefore represent a promising strategy to improve the efficacy of immunotherapy against desmoplastic cancers.
Project description:We studied the impact of a combination of chemotherapy and PD-1 immune checkpoint blockade on tumor progression in the PyMT mammary carcinoma mouse model compared to each treatment as monotherapy. To gain insight into the reasons underlying improved efficacy of combined chemoimmunotherapy, whole transcriptome profiling of tumors of mice receiving either a control antibody, anti-PD-1 antibody, doxorubicin chemotherapy + a control antibody or doxorubicin chemotherapy + anti-PD-1 antibody was performed via next generation mRNA sequencing, in triplicates, on a NextSeq 550 high-throughput bench top sequencer.
