Project description:Tumor cells orchestrate their microenvironment. Here, we provide biochemical, structural, functional and clinical evidence that Cathepsin S (CTSS) alterations induce a tumor-promoting immune microenvironment in follicular lymphoma (FL). We found CTSS mutations at Y132 in 6% of FL (19/305). Another 13% (37/286) had CTSS amplification, which was associated with higher CTSS expression. CTSS Y132 mutations lead to accelerated autocatalytic conversion from pro-CTSS to active CTSS and increase substrate cleavage, including CD74 which regulates MHC-II-restricted antigen presentation. Lymphoma cells with hyperactive CTSS more efficiently activated antigen-specific CD4+ T-cells in vitro. Tumors with hyperactive CTSS showed increased CD4+ T-cell infiltration and proinflammatory cytokine perturbation in a mouse model and in human FLs. In mice, this CTSS-induced immune microenvironment promoted tumor growth. Clinically, patients with CTSS-hyperactive FL had better treatment outcomes with standard immunochemotherapies, indicating that these immunosuppressive regimens target both the lymphoma cells and the tumor-promoting immune microenvironment. Digital multiplexed gene expression profiling of formalin-fixed and paraffin-embedded biopsy specimens of the GLSG2000 cohort was performed as previously described (Hellmuth et al., Blood 2018)
Project description:Tumor cells orchestrate their microenvironment. Here, we provide biochemical, structural, functional and clinical evidence that Cathepsin S (CTSS) alterations induce a tumor-promoting immune microenvironment in follicular lymphoma (FL). We found CTSS mutations at Y132 in 6% of FL (19/305). Another 13% (37/286) had CTSS amplification, which was associated with higher CTSS expression. CTSS Y132 mutations lead to accelerated autocatalytic conversion from pro-CTSS to active CTSS and increase substrate cleavage, including CD74 which regulates MHC-II-restricted antigen presentation. Lymphoma cells with hyperactive CTSS more efficiently activated antigen-specific CD4+ T-cells in vitro. Tumors with hyperactive CTSS showed increased CD4+ T-cell infiltration and proinflammatory cytokine perturbation in a mouse model and in human FLs. In mice, this CTSS-induced immune microenvironment promoted tumor growth. Clinically, patients with CTSS-hyperactive FL had better treatment outcomes with standard immunochemotherapies, indicating that these immunosuppressive regimens target both the lymphoma cells and the tumor-promoting immune microenvironment. Digital multiplexed gene expression profiling of formalin-fixed and paraffin-embedded biopsy specimens of the validation cohort was performed as previously described (Hellmuth et al., Blood 2018)
Project description:Our data showed that ENT broadly impacted multiple populations of immune cells within the TME. Thus, we performed general immune transcriptome profiling on whole tumors isolated from the neu-N model using a PanCancer immune-profiling gene panel for the NanoString platform.
Project description:nCounter platform from Nanostring Technologies (Mouse PanCancer Immune Profiling Panel) was used to assess differential gene expression between NT and Th17 cell treated B16F10 melanoma bearing mice in the tumor and tumor-draining lymph nodes.
Project description:We performed differential gene expression analysis using high throughput multiplex analysis via NanoString nCounter PanCancer Immune Profiling panel, which analyzes 770 genes related to cancer-immune pathways (cancer progression, chemokines and cytokines and their receptors, and innate and adaptive immune response). nSolver software was used to analyze the data and a heat map was generated to show differential expression of 770 genes. Further, using a fold cut-off of ≥2 and p-value <0.05, we observed that 4'-BR significantly modulated expression of multiple cancer immune genes.