Profiling of the immune microenvironment in FL [PanCancer Immune Profiling]

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) 54 fully assigned follicular lymphoma patient samples were analysed with the PanCancer 730 immune gene panel from NanoString.