HDAC Inhibition Increases CXCL12 Secretion to Recruit Natural Killer Cells in Peripheral T-cell Lymphoma.

Autor:	Zhu J; Shanghai Institute of Hematology, Blood and Marrow Transplantation Center, Collaborative Innovation Center of Hematology, Department of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.; State Key Laboratory of Bioactive Substance and Function of Natural Medicines, NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.; Department of Hematology, Shanghai Sixth People's Hospital, Shanghai Jiaotong University, Shanghai, China., Wang F; State Key Laboratory of Bioactive Substance and Function of Natural Medicines, NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China., Wang L; Shanghai Institute of Hematology, Blood and Marrow Transplantation Center, Collaborative Innovation Center of Hematology, Department of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Dai B; Department of Hematology, Huashan Hospital, Fudan University, Shanghai, China., Xu G; Shanghai Institute of Hematology, Blood and Marrow Transplantation Center, Collaborative Innovation Center of Hematology, Department of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Zhao L; State Key Laboratory of Bioactive Substance and Function of Natural Medicines, NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China., Jiang H; State Key Laboratory of Bioactive Substance and Function of Natural Medicines, NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China., Gao W; Shanghai Institute of Hematology, Blood and Marrow Transplantation Center, Collaborative Innovation Center of Hematology, Department of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Zhang T; State Key Laboratory of Bioactive Substance and Function of Natural Medicines, NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China., Zhao C; State Key Laboratory of Bioactive Substance and Function of Natural Medicines, NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China., Li YX; State Key Laboratory of Bioactive Substance and Function of Natural Medicines, NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China., Hu J; Shanghai Institute of Hematology, Blood and Marrow Transplantation Center, Collaborative Innovation Center of Hematology, Department of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Li K; State Key Laboratory of Bioactive Substance and Function of Natural Medicines, NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2024 Aug 01; Vol. 84 (15), pp. 2450-2467.
DOI:	10.1158/0008-5472.CAN-23-3250
Abstrakt:	Peripheral T-cell lymphoma (PTCL) is a heterogeneous and aggressive disease with a poor prognosis. Histone deacetylase (HDAC) inhibitors have shown inhibitory effects on PTCL. A better understanding of the therapeutic mechanism underlying the effects of HDAC inhibitors could help improve treatment strategies. Herein, we found that high expression of HDAC3 is associated with poor prognosis in PTCL. HDAC3 inhibition suppressed lymphoma growth in immunocompetent mice but not in immunodeficient mice. HDAC3 deletion delayed the progression of lymphoma, reduced the lymphoma burden in the thymus, spleen, and lymph nodes, and prolonged the survival of mice bearing N-methyl-N-nitrosourea-induced lymphoma. Furthermore, inhibiting HDAC3 promoted the infiltration and enhanced the function of natural killer (NK) cells. Mechanistically, HDAC3 mediated ATF3 deacetylation, enhancing its transcriptional inhibitory activity. Targeting HDAC3 enhanced CXCL12 secretion through an ATF3-dependent pathway to stimulate NK-cell recruitment and activation. Finally, HDAC3 suppression improved the response of PTCL to conventional chemotherapy. Collectively, this study provides insights into the mechanism by which HDAC3 regulates ATF3 activity and CXCL12 secretion, leading to immune infiltration and lymphoma suppression. Combining HDAC3 inhibitors with chemotherapy may be a promising strategy for treating PTCL. Significance: Targeting HDAC3 suppresses progression of T-cell lymphoma by activating ATF3 to induce secretion of CXCL12 and promote infiltration of NK cells, providing an immunostimulatory approach for treating T-cell lymphoma patients. (©2024 American Association for Cancer Research.)
Databáze:	MEDLINE
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