Somatic Mutations in Clonally Expanded T-lymphocytes in Patients with Chronic Graft-Versus-Host Disease
Giljun Park, et al.
Received Date: 12th August 19
Giljun Park, Daehong Kim, Jani Huuhtanen, Sofie Lundgren, Rajiv K. Khajuria, Ana M. Hurtado, Cecilia Muñoz-Calleja, Laura Cardeñoso, Valle Gómez-García de Soria, Tzu Hua Chen-Liang, Samuli Eldfors, Pekka Ellonen, Sari Hannula, Oscar Bruck, Anna Kreutzman, Urpu Salmenniemi, Tapio Lönnberg, Andres Jerez, Maija Itälä-Remes, Mikko A. I. Keränen, and Satu Mustjoki, MD
Graft-versus-host-disease (GvHD) is the main complication of allogeneic hematopoietic stem cell transplantation. GvHD patients have aberrant T cell expansions, which are thought to drive pathological immune activation. Here we report mechanistic insights that somatic mutations may account for persistent clonal T cell expansions in chronic GvHD (cGvHD). In an index patient suffering from cGVHD, we discovered persisting somatic MTOR, NFKB2, and TLR2 mutations in an expanded CD4+ T clone. In the screening cohort (n=135), the MTOR P2229R kinase domain mutation was detected in two additional cGvHD patients, but not in controls. Functional analysis of the discovered MTOR mutation indicated a gain-of-function alteration in translational regulation yielding in up-regulation of phosphorylated S6K1, S6, and AKT. Paired single-cell RNA and T cell receptor alpha and beta sequencing strongly supported cytotoxicity and abnormal proliferation of the clonally expanded CD4+ T cells. Real-time impedance measurements indicated increased cytotoxicity of mutated CD4 + T cells against the patient´s fibroblasts. High throughput drug-sensitivity testing suggested that mutations induce resistance to mTOR inhibitors but increase sensitivity for HSP90 inhibitors. Our findings suggest a novel explanation for the aberrant, persistent T cell activation in cGvHD, and pave the way for novel targeted therapies.
Read in full at bioRxiv.
This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.