Activation of STING by the novel liposomal TLC388 enhances the therapeutic response to anti-PD-1 antibodies in combination with radiotherapy.

Autor: Chen JY; Department of Biomedical Imaging and Radiological Science, China Medical University, Taichung, 40402, Taiwan.; Translation Research Core, China Medical University Hospital, China Medical University, Taichung, 40402, Taiwan., Lin PY; Proton Therapy and Science Center, China Medical University Hospital, China Medical University, Taichung, 40402, Taiwan R.O.C., Hong WZ; Proton Therapy and Science Center, China Medical University Hospital, China Medical University, Taichung, 40402, Taiwan R.O.C., Yang PC; Proton Therapy and Science Center, China Medical University Hospital, China Medical University, Taichung, 40402, Taiwan R.O.C., Chiang SF; Lab of Precision Medicine, Feng-Yuan Hospital, Ministry of Health and Welfare, Taichung, 42055, Taiwan., Chang HY; Proton Therapy and Science Center, China Medical University Hospital, China Medical University, Taichung, 40402, Taiwan R.O.C., Ke TW; Department of Colorectal Surgery, China Medical University Hospital, China Medical University, Taichung, 40402, Taiwan.; School of Chinese Medicine, China Medical University, Taichung, 40402, Taiwan., Liang JA; Department of Radiation Oncology, China Medical University Hospital, China Medical University, Taichung, Taiwan.; Department of Radiation Oncology, School of Medicine, China Medical University, Taichung, 40402, Taiwan., Chen WT; Department of Colorectal Surgery, China Medical University Hospital, China Medical University, Taichung, 40402, Taiwan.; Department of Colorectal Surgery, China Medical University HsinChu Hospital, China Medical University, HsinChu, 302, Taiwan.; School of Medicine, China Medical University, Taichung, 40402, Taiwan., Chao KSC; Proton Therapy and Science Center, China Medical University Hospital, China Medical University, Taichung, 40402, Taiwan R.O.C.. 094032@tool.caaumed.org.tw.; Department of Radiation Oncology, China Medical University Hospital, China Medical University, Taichung, Taiwan. 094032@tool.caaumed.org.tw.; Department of Radiation Oncology, School of Medicine, China Medical University, Taichung, 40402, Taiwan. 094032@tool.caaumed.org.tw., Huang KC; Department of Biomedical Imaging and Radiological Science, China Medical University, Taichung, 40402, Taiwan. chihyang0425@mail.cmu.edu.tw.; Translation Research Core, China Medical University Hospital, China Medical University, Taichung, 40402, Taiwan. chihyang0425@mail.cmu.edu.tw.; Cancer Biology and Precision Therapeutics Center, China Medical University, Taichung, 40402, Taiwan. chihyang0425@mail.cmu.edu.tw.
Jazyk: angličtina
Zdroj: Cancer immunology, immunotherapy : CII [Cancer Immunol Immunother] 2024 Apr 02; Vol. 73 (5), pp. 92. Date of Electronic Publication: 2024 Apr 02.
DOI: 10.1007/s00262-024-03692-8
Abstrakt: Current immune checkpoint inhibiters (ICIs) have contrasting clinical results in poorly immunogenic cancers such as microsatellite-stable colorectal cancer (MSS-CRC). Therefore, understanding and developing the combinational therapeutics for ICI-unresponsive cancers is critical. Here, we demonstrated that the novel topoisomerase I inhibitor TLC388 can reshape the tumor immune landscape, corroborating their antitumor effects combined with radiotherapy as well as immunotherapy. We found that TLC388 significantly triggered cytosolic single-stranded DNA (ssDNA) accumulation for STING activation, leading to type I interferons (IFN-Is) production for increased cancer immunogenicity to enhance antitumor immunity. TLC388-treated tumors were infiltrated by a vast number of dendritic cells, immune cells, and costimulatory molecules, contributing to the favorable antitumor immune response within the tumor microenvironment. The infiltration of cytotoxic T and NK cells were more profoundly existed within tumors in combination with radiotherapy and ICIs, leading to superior therapeutic efficacy in poorly immunogenic MSS-CRC. Taken together, these results showed that the novel topoisomerase I inhibitor TLC388 increased cancer immunogenicity by ssDNA/STING-mediated IFN-I production, enhancing antitumor immunity for better therapeutic efficacy in combination with radiotherapy and ICIs for poorly immunogenic cancer.
(© 2024. The Author(s).)
Databáze: MEDLINE
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