TY - JOUR
T1 - NKp44-based chimeric antigen receptor effectively redirects primary T cells against synovial sarcoma
AU - Murayama, Yudai
AU - Kasahara, Yasushi
AU - Kubo, Nobuhiro
AU - Shin, Chansu
AU - Imamura, Masaru
AU - Oike, Naoki
AU - Ariizumi, Takashi
AU - Saitoh, Akihiko
AU - Baba, Minori
AU - Miyazaki, Tomohiro
AU - Suzuki, Yuko
AU - Ling, Yiwei
AU - Okuda, Shujiro
AU - Mihara, Keichiro
AU - Ogose, Akira
AU - Kawashima, Hiroyuki
AU - Imai, Chihaya
N1 - Publisher Copyright:
© 2022
PY - 2022/11
Y1 - 2022/11
N2 - Background: T-cell receptor-engineered T-cell therapies have achieved promising response rates against synovial sarcoma in clinical trials, but their applicability is limited owing to the HLA matching requirement. Chimeric antigen receptor (CAR) can redirect primary T cells to tumor-associated antigens without requiring HLA matching. However, various obstacles, including the paucity of targetable antigens, must be addressed for synovial sarcoma. Ligands for natural killer (NK) cell-activating receptors are highly expressed by tumor cells. Methods: The surface expression of ligands for NK cell-activating receptors in synovial sarcoma cell lines was analyzed. We analyzed RNA sequencing data deposited in a public database to evaluate NKp44-ligand expression. Primary T cells retrovirally transduced with CAR targeting NKp44 ligands were evaluated for their functions in synovial sarcoma cells. Alterations induced by various stimuli, including a histone deacetylase inhibitor, a hypomethylating agent, inflammatory cytokines, and ionizing radiation, in the expression levels of NKp44 ligands were investigated. Results:: Ligands for NKp44 and NKp30 were expressed in all cell lines. NKG2D ligands were barely expressed in a single cell line. None of the cell lines expressed NKp46 ligand. Primary synovial sarcoma cells expressed the mRNA of the truncated isoform of MLL5, a known cellular ligand for NKp44. NKp44-based CAR T cells specifically recognize synovial sarcoma cells, secrete interferon-γ, and exert suppressive effects on tumor cell growth. No stimulus altered the expression of NKp44 ligands. Conclusion: NKp44-based CAR T cells can redirect primary human T cells to synovial sarcoma cells. CAR-based cell therapies may be an option for treating synovial sarcomas.
AB - Background: T-cell receptor-engineered T-cell therapies have achieved promising response rates against synovial sarcoma in clinical trials, but their applicability is limited owing to the HLA matching requirement. Chimeric antigen receptor (CAR) can redirect primary T cells to tumor-associated antigens without requiring HLA matching. However, various obstacles, including the paucity of targetable antigens, must be addressed for synovial sarcoma. Ligands for natural killer (NK) cell-activating receptors are highly expressed by tumor cells. Methods: The surface expression of ligands for NK cell-activating receptors in synovial sarcoma cell lines was analyzed. We analyzed RNA sequencing data deposited in a public database to evaluate NKp44-ligand expression. Primary T cells retrovirally transduced with CAR targeting NKp44 ligands were evaluated for their functions in synovial sarcoma cells. Alterations induced by various stimuli, including a histone deacetylase inhibitor, a hypomethylating agent, inflammatory cytokines, and ionizing radiation, in the expression levels of NKp44 ligands were investigated. Results:: Ligands for NKp44 and NKp30 were expressed in all cell lines. NKG2D ligands were barely expressed in a single cell line. None of the cell lines expressed NKp46 ligand. Primary synovial sarcoma cells expressed the mRNA of the truncated isoform of MLL5, a known cellular ligand for NKp44. NKp44-based CAR T cells specifically recognize synovial sarcoma cells, secrete interferon-γ, and exert suppressive effects on tumor cell growth. No stimulus altered the expression of NKp44 ligands. Conclusion: NKp44-based CAR T cells can redirect primary human T cells to synovial sarcoma cells. CAR-based cell therapies may be an option for treating synovial sarcomas.
KW - Chimeric antigen receptor
KW - Immunotherapy
KW - NKp44
KW - Synovial sarcoma
KW - T-cell therapies
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U2 - 10.1016/j.tranon.2022.101521
DO - 10.1016/j.tranon.2022.101521
M3 - Article
AN - SCOPUS:85136144625
SN - 1944-7124
VL - 25
JO - Translational Oncology
JF - Translational Oncology
M1 - 101521
ER -