BTLA dysregulation correlates with poor outcome and diminished T cell-mediated antitumor responses in chronic lymphocytic leukemia

• Published in: Cancer Immunology, Immunotherapy Vol. 72; no. 7; pp. 2529 - 2539
• Main Authors: Sordo-Bahamonde, Christian, Lorenzo-Herrero, Seila, Martínez-Pérez, Alejandra, Gonzalez-Rodriguez, Ana P., Payer, Ángel R., González-García, Esther, Aguilar-García, Candelaria, González-Rodríguez, Sara, López-Soto, Alejandro, García-Torre, Alejandra, Gonzalez, Segundo
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.07.2023; Springer Nature B.V
• Subjects: Antigens, CD19 - metabolism; Antitumor activity; Brief Report; BTLA protein; Cancer Research; CD19 antigen; CD3 antigen; CD4 antigen; CD4-Positive T-Lymphocytes; CD8 antigen; CD8-Positive T-Lymphocytes; Chronic lymphocytic leukemia; Humans; Immune checkpoint; Immunology; Immunosuppression; Interleukin 2; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell - metabolism; Lymphocytes; Lymphocytes T; Medicine; Medicine & Public Health; Monoclonal antibodies; Oncology; Receptors, Immunologic - metabolism; γ-Interferon; BTLA; CLL; Checkpoint; HVEM; Leukemia; T cell
• ISSN: 0340-7004; 1432-0851
• DOI: 10.1007/s00262-023-03435-1

Patients with chronic lymphocytic leukemia (CLL) progressively develop marked immunosuppression, dampening innate and adaptive-driven antitumor responses. However, the underlying mechanisms promoting immune exhaustion are largely unknown. Herein, we provide new insights into the role of BTLA/HVEM axis promoting defects in T cell-mediated responses against leukemic cells. Increased expression of BTLA, an inhibitory immune checkpoint, was detected on the surface of CD4 + and CD8 + T lymphocytes in patients with CLL. Moreover, high levels of BTLA on CD4 + T cells correlated with diminished time to treatment. Signaling through BTLA activation led to decreased IL-2 and IFN-γ production ex vivo, whereas BTLA/HVEM binding disruption enhanced IFN-γ + CD8 + T lymphocytes. Accordingly, BTLA blockade in combination with bispecific anti-CD3/anti-CD19 antibody promoted CD8 + T cell-mediated anti-leukemic responses. Finally, treatment with an anti-BLTA blocking monoclonal antibody alone or in combination with ibrutinib-induced leukemic cell depletion in vitro. Altogether, our data reveal that BTLA dysregulation has a prognostic role and is limiting T cell-driven antitumor responses, thus providing new insights about immune exhaustion in patients with CLL.