AXL Inhibition Improves the Antitumor Activity of Chimeric Antigen Receptor T Cells.

Autor:	Sakemura RL; T Cell Engineering, Mayo Clinic, Rochester, Minnesota.; Division of Hematology, Mayo Clinic, Rochester, Minnesota., Hefazi M; T Cell Engineering, Mayo Clinic, Rochester, Minnesota.; Division of Hematology, Mayo Clinic, Rochester, Minnesota., Cox MJ; T Cell Engineering, Mayo Clinic, Rochester, Minnesota., Siegler EL; T Cell Engineering, Mayo Clinic, Rochester, Minnesota.; Division of Hematology, Mayo Clinic, Rochester, Minnesota., Sinha S; Division of Hematology, Mayo Clinic, Rochester, Minnesota., Hansen MJ; Department of Immunology, Mayo Clinic, Rochester, Minnesota., Stewart CM; T Cell Engineering, Mayo Clinic, Rochester, Minnesota.; Division of Hematology, Mayo Clinic, Rochester, Minnesota.; Mayo Clinic Graduate School of Biomedical Sciences, Rochester, Minnesota.; Department of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota., Feigin JM; T Cell Engineering, Mayo Clinic, Rochester, Minnesota., Manriquez Roman C; T Cell Engineering, Mayo Clinic, Rochester, Minnesota.; Division of Hematology, Mayo Clinic, Rochester, Minnesota.; Mayo Clinic Graduate School of Biomedical Sciences, Rochester, Minnesota.; Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota., Schick KJ; T Cell Engineering, Mayo Clinic, Rochester, Minnesota., Can I; T Cell Engineering, Mayo Clinic, Rochester, Minnesota.; Division of Hematology, Mayo Clinic, Rochester, Minnesota., Tapper EE; T Cell Engineering, Mayo Clinic, Rochester, Minnesota., Horvei P; T Cell Engineering, Mayo Clinic, Rochester, Minnesota., Adada MM; T Cell Engineering, Mayo Clinic, Rochester, Minnesota.; Division of Hematology, Mayo Clinic, Rochester, Minnesota., Bezerra ED; T Cell Engineering, Mayo Clinic, Rochester, Minnesota., Kankeu Fonkoua LA; T Cell Engineering, Mayo Clinic, Rochester, Minnesota.; Division of Hematology, Mayo Clinic, Rochester, Minnesota., Ruff MW; T Cell Engineering, Mayo Clinic, Rochester, Minnesota.; Department of Neurology, Mayo Clinic, Rochester, Minnesota., Forsman CL; T Cell Engineering, Mayo Clinic, Rochester, Minnesota., Nevala WK; Department of Immunology, Mayo Clinic, Rochester, Minnesota., Boysen JC; Division of Hematology, Mayo Clinic, Rochester, Minnesota., Tschumper RC; Department of Immunology, Mayo Clinic, Rochester, Minnesota., Grand CL; Sumitomo Dainippon Pharma Oncology, Inc. Lehi, Utah., Kuchimanchi KR; Sumitomo Dainippon Pharma Oncology, Inc. Lehi, Utah., Mouritsen L; Sumitomo Dainippon Pharma Oncology, Inc. Lehi, Utah., Foulks JM; Sumitomo Dainippon Pharma Oncology, Inc. Lehi, Utah., Warner SL; Sumitomo Dainippon Pharma Oncology, Inc. Lehi, Utah., Call TG; Division of Hematology, Mayo Clinic, Rochester, Minnesota., Parikh SA; Division of Hematology, Mayo Clinic, Rochester, Minnesota., Ding W; Division of Hematology, Mayo Clinic, Rochester, Minnesota., Kay NE; Division of Hematology, Mayo Clinic, Rochester, Minnesota., Kenderian SS; T Cell Engineering, Mayo Clinic, Rochester, Minnesota.; Division of Hematology, Mayo Clinic, Rochester, Minnesota.; Department of Immunology, Mayo Clinic, Rochester, Minnesota.; Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota.
Jazyk:	angličtina
Zdroj:	Cancer immunology research [Cancer Immunol Res] 2023 Sep 01; Vol. 11 (9), pp. 1222-1236.
DOI:	10.1158/2326-6066.CIR-22-0254
Abstrakt:	The receptor tyrosine kinase AXL is a member of the TYRO3, AXL, and proto-oncogene tyrosine-protein kinase MER family and plays pleiotropic roles in cancer progression. AXL is expressed in immunosuppressive cells, which contributes to decreased efficacy of immunotherapy. Therefore, we hypothesized that AXL inhibition could serve as a strategy to overcome resistance to chimeric antigen receptor T (CAR T)-cell therapy. To test this, we determined the impact of AXL inhibition on CD19-targeted CAR T (CART19)-cell functions. Our results demonstrate that T cells and CAR T cells express high levels of AXL. Specifically, higher levels of AXL on activated Th2 CAR T cells and M2-polarized macrophages were observed. AXL inhibition with small molecules or via genetic disruption in T cells demonstrated selective inhibition of Th2 CAR T cells, reduction of Th2 cytokines, reversal of CAR T-cell inhibition, and promotion of CAR T-cell effector functions. AXL inhibition is a novel strategy to enhance CAR T-cell functions through two independent, but complementary, mechanisms: targeting Th2 cells and reversing myeloid-induced CAR T-cell inhibition through selective targeting of M2-polarized macrophages. (©2023 American Association for Cancer Research.)
Databáze:	MEDLINE
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