2. Academic Validation
  3. CD155 and CD112 as possible therapeutic targets of FLT3 inhibitors for acute myeloid leukemia

CD155 and CD112 as possible therapeutic targets of FLT3 inhibitors for acute myeloid leukemia

  • Oncol Lett. 2022 Feb;23(2):51. doi: 10.3892/ol.2021.13169.
Yuta Kaito 1,  Mitsuhito Hirano 2,  Muneyoshi Futami 2,  Masanori Nojima 3,  Hideto Tamura 4,  Arinobu Tojo 1 2,  Yoichi Imai 1
Affiliations

Affiliations

  • 1 Department of Hematology/Oncology, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
  • 2 Department of Molecular Therapy, Advanced Clinical Research Center, The University of Tokyo, Tokyo 108-8639, Japan.
  • 3 Department of Translational Research, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
  • 4 Department of Hematology, Saitama Medical Center, Dokkyo Medical University, Saitama 343-8555, Japan.
PMID: 34992684 DOI: 10.3892/ol.2021.13169
Abstract

Acute myeloid leukemia (AML) relapse is considered to be related to escape from antitumor immunity. Changes in the expression of immune checkpoints, including B7 homolog (H)1 and B7-H2, have been reported to contribute to AML progression. Binding of T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) among Other immune checkpoints on natural killer (NK) and T cells to CD155/CD112 in tumors is supposed to be inhibitory; however, the mechanism by which changes in CD155 and CD112 expression affect tumor immunity remains unclear. When the increased expression of CD155 and CD112 activates Raf-MEK-ERK pathway and Raf-MEK-ERK pathway is one of the targets of FMS-like tyrosine kinase 3 (FLT3) inhibition. The present study investigated the alterations in CD155 and CD112 expression under FLT3 inhibition (quizartinib and gilteritinib) and studied its effect on NK and T cell cytotoxicity. CD155 and CD112 expression was analyzed using flow cytometry and reverse transcription-quantitative PCR in AML cell lines with or without FLT3 mutation using FLT3 inhibitors. CD155 and CD112 expression was specifically downregulated by FLT3 inhibition in FLT3-mutated cell lines. Direct cytotoxicity and antibody-dependent cellular cytotoxicity against these cells by NK cells were enhanced. However, the cytotoxicity of γδ T cells with low TIGIT expression compared with NK cells was not enhanced in direct cytotoxicity assay using luciferase luminescence. The analysis of clinical trials from The Cancer Genome Atlas (TCGA) revealed that high CD155 and CD112 expression is associated with poor overall survival. The enhanced cytotoxicity of NK cells against CD155- and CD112-downregulated cells following FLT3 inhibition indicated CD155 and CD112 as possible targets of immunotherapy for AML using FLT3 inhibitors.

Keywords

CD112; CD155; FMS-like tyrosine kinase 3 inhibitor; acute myeloid leukemia; immune checkpoint; natural killer cell.

Figures
Products