2. Academic Validation
  3. BTLA dysregulation correlates with poor outcome and diminished T cell-mediated antitumor responses in chronic lymphocytic leukemia

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

  • Cancer Immunol Immunother. 2023 Apr 11. doi: 10.1007/s00262-023-03435-1.
Christian Sordo-Bahamonde 1 2 3,  Seila Lorenzo-Herrero 4 5 6,  Alejandra Martínez-Pérez 4 5 6,  Ana P Gonzalez-Rodriguez 5 6 7,  Ángel R Payer 5 6 7,  Esther González-García 5 6 8,  Candelaria Aguilar-García 4 5 6,  Sara González-Rodríguez 5 6 9,  Alejandro López-Soto 5 6 10,  Alejandra García-Torre 11,  Segundo Gonzalez 12 13 14
Affiliations

Affiliations

  • 1 Department of Functional Biology, Immunology, Universidad de Oviedo, 33006, Oviedo, Spain. [email protected].
  • 2 Instituto Universitario de Oncología del Principado de Asturias (IUOPA), 33006, Oviedo, Spain. [email protected].
  • 3 Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011, Oviedo, Spain. [email protected].
  • 4 Department of Functional Biology, Immunology, Universidad de Oviedo, 33006, Oviedo, Spain.
  • 5 Instituto Universitario de Oncología del Principado de Asturias (IUOPA), 33006, Oviedo, Spain.
  • 6 Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011, Oviedo, Spain.
  • 7 Department of Hematology, Hospital Universitario Central de Asturias (HUCA), 33011, Oviedo, Spain.
  • 8 Department of Hematology, Hospital de Cabueñes, 33203, Gijón, Spain.
  • 9 Department of Medicine, Universidad de Oviedo, 33006, PharmacologyOviedo, Spain.
  • 10 Department of Biochemistry and Molecular Biology, Universidad of Oviedo, 33006, Oviedo, Spain.
  • 11 Department of Immunology, Hospital Universitario Central de Asturias (HUCA), Oviedo, Spain.
  • 12 Department of Functional Biology, Immunology, Universidad de Oviedo, 33006, Oviedo, Spain. [email protected].
  • 13 Instituto Universitario de Oncología del Principado de Asturias (IUOPA), 33006, Oviedo, Spain. [email protected].
  • 14 Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011, Oviedo, Spain. [email protected].
PMID: 37041226 DOI: 10.1007/s00262-023-03435-1
Abstract

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.

Keywords

BTLA; CLL; Checkpoint; HVEM; Leukemia; T cell.

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