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

• Published in: Oncology letters Vol. 23; no. 2; p. 51
• Main Authors: Kaito, Yuta, Hirano, Mitsuhito, Futami, Muneyoshi, Nojima, Masanori, Tamura, Hideto, Tojo, Arinobu, Imai, Yoichi
• Format: Journal Article
• Language: English
• Published: Greece Spandidos Publications UK Ltd 01.02.2022; D.A. Spandidos
• Subjects: Antibodies; Chemicals; Experiments; Flow cytometry; Kinases; Laboratories; Lasers; Leukemia; Ligands; Lymphocytes; Mutation; Oncology; Plasmids; Software; United States > US; FMS-like tyrosine kinase 3 inhibitor; acute myeloid leukemia; natural killer cell; CD112; immune checkpoint; CD155
• ISSN: 1792-1074; 1792-1082
• DOI: 10.3892/ol.2021.13169

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 ( ) inhibition. The present study investigated the alterations in CD155 and CD112 expression under 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 mutation using inhibitors. CD155 and CD112 expression was specifically downregulated by inhibition in -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 inhibition indicated CD155 and CD112 as possible targets of immunotherapy for AML using inhibitors.