BTLA/HVEM Axis Induces NK Cell Immunosuppression and Poor Outcome in Chronic Lymphocytic Leukemia

Cancers

Seila Lorenzo-Herrero¹  Segundo Gonzalez¹  Christian Sordo-Bahamonde¹  Esther González-García²  Angel R. Payer³  AnaP. Gonzalez-Rodriguez³  Alejandro López-Soto³ 

[1] Department of Functional Biology, Immunology, Universidad de Oviedo, 33006 Oviedo, Spain;Department of Hematology, Hospital de Cabueñes, 33203 Gijón, Spain;Instituto Universitario de Oncología del Principado de Asturias (IUOPA), 33006 Oviedo, Spain;

关键词: chronic lymphocytic leukemia;    CLL;    BTLA;    HVEM;    TNFRSF14;    CD270;   

DOI  :  10.3390/cancers13081766

来源: DOAJ

【 摘 要 】

Chronic lymphocytic leukemia (CLL) is characterized by progressive immunosuppression and diminished cancer immunosurveillance. Immune checkpoint blockade (ICB)-based therapies, a major breakthrough against cancer, have emerged as a powerful tool to reinvigorate antitumor responses. Herein, we analyzed the role of the novel inhibitory checkpoint BTLA and its ligand, HVEM, in the regulation of leukemic and natural killer (NK) cells in CLL. Flow cytometry analyses showed that BTLA expression is upregulated on leukemic cells and NK cells from patients with CLL, whereas HVEM is downregulated only in leukemic cells, especially in patients with advanced Rai-Binet stage. In silico analysis revealed that increased HVEM, but not BTLA, mRNA expression in leukemic cells correlated with diminished overall survival. Further, soluble BTLA (sBTLA) was found to be increased in the sera of patients with CLL and highly correlated with poor prognostic markers and shorter time to treatment. BTLA blockade with an anti-BTLA monoclonal antibody depleted leukemic cells and boosted NK cell-mediated responses ex vivo by increasing their IFN-γ production, cytotoxic capability, and antibody-dependent cytotoxicity (ADCC). In agreement with an inhibitory role of BTLA in NK cells, surface BTLA expression on NK cells was associated with poor outcome in patients with CLL. Overall, this study is the first to bring to light a role of BTLA/HVEM in the suppression of NK cell-mediated immune responses in CLL and its impact on patient’s prognosis, suggesting that BTLA/HVEM axis may be a potential therapeutic target in this disease.

【 授权许可】

Unknown