Unprocessed data for: Cathepsin S Alterations Induce a Tumor-Promoting Immune Microenvironment in Follicular Lymphoma

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-IIrestricted
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.