FLT3-ITD Induces CMTM6 and Enhances Immune Escape in Acute Myeloid Leukemia.

Abstract

FMS-like tyrosine kinase-3 internal tandem duplication (FLT3-ITD) mutations are frequent in acute myeloid leukemia (AML) and are associated with a high risk of relapse. CKLF-like MARVEL transmembrane domain containing member 6 (CMTM6) stabilizes PD-L1 surface expression and modulates tumor immunity in solid cancer. In this study, we found a role for FLT3-induced CMTM6 in hematologic malignancies. FLT3 drove CMTM6 and PD-L1 expression in AML cells, whereas FLT3 inhibition reduced expression of CMTM6 and PD-L1. In three distinct allogeneic hematopoietic cell transplantation mouse models, transplantation of Cmtm6-deficient FLT3-ITD+ leukemia cells resulted in prolonged survival, reduced leukemia burden, enhanced T-cell effector function, and decreased expression of T-cell exhaustion markers compared with Cmtm6-proficient FLT3-ITD+ leukemia cells. Furthermore, combination therapy with anti-PD-L1 and tandutinib significantly improved survival, suppressed leukemia cell expansion, and augmented the anti-leukemia T-cell response in mice bearing FLT3-ITD+ leukemia. Mechanistically, protein-protein interaction of FLT3 and CMTM6 within their transmembrane domains, which was not phosphorylation dependent, enhanced CMTM6 stability in leukemia cells, whereas FLT3-ITD did not increase CMTM6 and PD-L1 expression at the RNA level. Furthermore, CMTM6 upregulation and protein interaction with FLT3 were validated in primary leukemia cells from two independent cohorts of patients with FLT3-ITD+ AML. Collectively, these findings uncover FLT3-mediated stabilization of CMTM6 in AML cells, which results in enhanced PD-L1 cell surface expression and leukemia immune escape. Activation of the CMTM6/PD-L1 axis in FLT3-ITD-driven acute myeloid leukemia mediates immunosuppression, providing the basis for potential inhibition of this pathway to harness antitumor immunity.