Project description:DeepNeo predicts immunogenic neoantigens for both MHC I and II responsive to immune checkpoint blockade therapy. Furthermore, spontaneous immunity was observed in pancancer manner for MHC II.
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: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:Combination checkpoint blockade with anti-PD-1 and anti-CTLA-4 antibodies has shown promising efficacy in melanoma. However, the underlying mechanism in humans remains unclear. We performed RNA+TCR single-cell analysis across time in 36 stage IV melanoma patients treated with anti-PD-1, anti-CTLA-4, or combination therapy. We developed the algorithm Cyclone to track temporal clonal dynamics and underlying cell states. Checkpoint blockade induced waves of clonal T cell responses that peaked at distinct timepoints. Combination therapy resulted in greater magnitude of clonal responses at 6 and 9 weeks compared to single-agent therapies, including melanoma-specific CD8 T cells and exhausted CD8 T cell (TEX) clones. Focused analyses of TEX identified that anti-CTLA-4 induced robust expansion and proliferation of progenitor TEX, which synergized with anti-PD-1 to reinvigorate TEX during combination therapy. These next generation immune profiling approaches can guide the selection of drugs, schedule, and dosing for novel combination strategies.
Project description:Combination checkpoint blockade with anti-PD-1 and anti-CTLA-4 antibodies has shown promising efficacy in melanoma. However, the underlying mechanism in humans remains unclear. We performed RNA+TCR single-cell analysis across time in 36 stage IV melanoma patients treated with anti-PD-1, anti-CTLA-4, or combination therapy. We developed the algorithm Cyclone to track temporal clonal dynamics and underlying cell states. Checkpoint blockade induced waves of clonal T cell responses that peaked at distinct timepoints. Combination therapy resulted in greater magnitude of clonal responses at 6 and 9 weeks compared to single-agent therapies, including melanoma-specific CD8 T cells and exhausted CD8 T cell (TEX) clones. Focused analyses of TEX identified that anti-CTLA-4 induced robust expansion and proliferation of progenitor TEX, which synergized with anti-PD-1 to reinvigorate TEX during combination therapy. These next generation immune profiling approaches can guide the selection of drugs, schedule, and dosing for novel combination strategies.
