Project description:Combinatorial Immunotherapy Induces Tumor Infiltrating CD8+ T Cells with Distinct Functional, Migratory, and Stem-Like Properties III
Project description:Combinatorial Immunotherapy Induces Tumor Infiltrating CD8+ T Cells with Distinct Functional, Migratory, and Stem-Like Properties I
Project description:This study reveals supeior efficiacy of triple combination treatment (TCT) based on anti-PD-(L)1 and anti-4-1BB/OX40 and describes immunological mechanisms underlying synergism between the treatment components
Project description:This study reveals supeior efficiacy of triple combination treatment (TCT) based on anti-PD-(L)1 and anti-4-1BB/OX40 and describes immunological mechanisms underlying synergism between the treatment components
Project description:This study reveals supeior efficiacy of triple combination treatment (TCT) based on anti-PD-(L)1 and anti-4-1BB/OX40 and describes immunological mechanisms underlying synergism between the treatment components
Project description:We devise Multiplex Universal Combinatorial Immunotherapy via Gene-silencing (MUCIG), as a versatile approach for combinatorial cancer immunotherapy. We harness CRISPR-Cas13d to efficiently target multiple endogenous immunosuppressive genes on demand, allowing us to silence various combinations of multiple immunosuppressive factors in the TME. Intra-tumoral AAV-mediated administration of MUCIG elicits significant anti-tumor activity with several Cas13d gRNA compositions (AAV-Cas13d-MUCIG). Optimization of TME targets by expression analysis led to a simplified off-the-shelf MUCIG targeting a four gene combination (PGGC: Pdl1/Cd274, Galectin9/Lgals9, Galectin3/Lgals3 and Cd47). AAV-Cas13d-PGGC showed significant in vivo anti-tumor efficacy in syngeneic tumor models. Single cell and flow profiling revealed that AAV-Cas13d-PGGC remodeled the TME by increasing CD8+ T cell infiltration and reducing neutrophils. MUCIG thus serves as a universal method to silence multiple immune genes in vivo, and can be delivered via AAV as a therapeutic approach. We devised an approach MUCIG (Multiplex Universal Combinatorial Immunotherapy via Gene-silencing) and designed MUCIG for targeting immunosuppressive genes at different scales of library pools. The first MUCIG pool included 313 genes selected based on these criteria. Subsequently, with a tiered approach, we designed three additional MUCIG pools (pool2: 152 genes; pool3: 55 genes; pool4: 19 genes). The distribution and coverage of gRNAs across all four pools were verified, confirming the robustness and specificity of this approach in the context of cancer immunosuppressive gene targeting therapy.
Project description:Metastatic uveal melanoma generally responds poorly to immunotherapy. The aim here was to sequence tumor-infiltrating lymphocytes from uveal melanoma metastases to study their phenotypes and T-cell receptor (TCR) clonotypes. We performed paired single-cell transcriptome and TCR sequencing using the 10x Genomics platform of IL2-expanded tumor-infiltrating lymphocytes from 7 liver and 1 subcutaneous metastasis.