LTX-315 triggers anticancer immunity by inducing MyD88-dependent maturation of dendritic cells
LTX-315 is a synthetic cationic oncolytic peptide with potent anticancer activity but limited toxicity for non-malignant cells. LTX-315 induces both immunogenic tumor cell death and generation of tumor-specific immune responses in multiple experimental tumor models. Given the central role of dendrit...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2024-03-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1332922/full |
| _version_ | 1797263316860534784 |
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| author | Xiao-Qing Li Xiao-Qing Li Takahiro Yamazaki Tianzhen He Md Masud Alam Jia Liu Anna L. Trivett Baldur Sveinbjørnsson Øystein Rekdal Lorenzo Galluzzi Lorenzo Galluzzi Lorenzo Galluzzi Joost J. Oppenheim De Yang |
| author_facet | Xiao-Qing Li Xiao-Qing Li Takahiro Yamazaki Tianzhen He Md Masud Alam Jia Liu Anna L. Trivett Baldur Sveinbjørnsson Øystein Rekdal Lorenzo Galluzzi Lorenzo Galluzzi Lorenzo Galluzzi Joost J. Oppenheim De Yang |
| author_sort | Xiao-Qing Li |
| collection | DOAJ |
| description | LTX-315 is a synthetic cationic oncolytic peptide with potent anticancer activity but limited toxicity for non-malignant cells. LTX-315 induces both immunogenic tumor cell death and generation of tumor-specific immune responses in multiple experimental tumor models. Given the central role of dendritic cell (DC) maturation in the induction of antigen-specific immunity, we investigated the effect of LTX-315 treatment on the maturation of tumor-infiltrating DCs (TiDCs) and the generation of anti-melanoma immunity. We found that LTX-315 treatment induces the maturation of DCs, both indirectly through the release of cancer cell-derived damage-associated molecular patterns (DAMPs)/alarmins and nucleic acids (DNA and RNA) capable of triggering distinct Toll-like receptor (TLR) signaling, and, directly by activating TLR7. The latter results in the ignition of multiple intracellular signaling pathways that promotes DC maturation, including NF-κB, mitogen activated protein kinases (MAPKs), and inflammasome signaling, as well as increased type 1 interferon production. Critically, the effects of LTX-315 on DCs the consequent promotion of anti-melanoma immunity depend on the cytosolic signal transducer myeloid differentiation response gene 88 (MyD88). These results cast light on the mechanisms by which LTX-315 induces DC maturation and hence elicits anticancer immunity, with important implications for the use of LTX-315 as an anticancer immunotherapeutic. |
| first_indexed | 2024-04-25T00:11:05Z |
| format | Article |
| id | doaj.art-38be6eb6a7bf4036a60a9ac668042e62 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-25T00:11:05Z |
| publishDate | 2024-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-38be6eb6a7bf4036a60a9ac668042e622024-03-13T12:52:09ZengFrontiers Media S.A.Frontiers in Immunology1664-32242024-03-011510.3389/fimmu.2024.13329221332922LTX-315 triggers anticancer immunity by inducing MyD88-dependent maturation of dendritic cellsXiao-Qing Li0Xiao-Qing Li1Takahiro Yamazaki2Tianzhen He3Md Masud Alam4Jia Liu5Anna L. Trivett6Baldur Sveinbjørnsson7Øystein Rekdal8Lorenzo Galluzzi9Lorenzo Galluzzi10Lorenzo Galluzzi11Joost J. Oppenheim12De Yang13Department of Biochemistry and Molecular Biology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin Medical University, Tianjin, ChinaLaboratory of Cancer Innovation, Frederick National Laboratory for Cancer Research, Center for Cancer Research, National Cancer Institute, Frederick, MD, United StatesDepartment of Radiation Oncology, Weill Cornell Medical College, New York, NY, United StatesLaboratory of Cancer Innovation, Frederick National Laboratory for Cancer Research, Center for Cancer Research, National Cancer Institute, Frederick, MD, United StatesLaboratory of Cancer Innovation, Frederick National Laboratory for Cancer Research, Center for Cancer Research, National Cancer Institute, Frederick, MD, United StatesLaboratory of Cancer Innovation, Frederick National Laboratory for Cancer Research, Center for Cancer Research, National Cancer Institute, Frederick, MD, United StatesLaboratory of Cancer Innovation, Frederick National Laboratory for Cancer Research, Center for Cancer Research, National Cancer Institute, Frederick, MD, United StatesLytix Biopharma, Oslo, NorwayLytix Biopharma, Oslo, NorwayDepartment of Radiation Oncology, Weill Cornell Medical College, New York, NY, United StatesSandra and Edward Meyer Cancer Center, New York, NY, United StatesCaryl and Israel Englander Institute for Precision Medicine, New York, NY, United StatesLaboratory of Cancer Innovation, Frederick National Laboratory for Cancer Research, Center for Cancer Research, National Cancer Institute, Frederick, MD, United StatesLaboratory of Cancer Innovation, Frederick National Laboratory for Cancer Research, Center for Cancer Research, National Cancer Institute, Frederick, MD, United StatesLTX-315 is a synthetic cationic oncolytic peptide with potent anticancer activity but limited toxicity for non-malignant cells. LTX-315 induces both immunogenic tumor cell death and generation of tumor-specific immune responses in multiple experimental tumor models. Given the central role of dendritic cell (DC) maturation in the induction of antigen-specific immunity, we investigated the effect of LTX-315 treatment on the maturation of tumor-infiltrating DCs (TiDCs) and the generation of anti-melanoma immunity. We found that LTX-315 treatment induces the maturation of DCs, both indirectly through the release of cancer cell-derived damage-associated molecular patterns (DAMPs)/alarmins and nucleic acids (DNA and RNA) capable of triggering distinct Toll-like receptor (TLR) signaling, and, directly by activating TLR7. The latter results in the ignition of multiple intracellular signaling pathways that promotes DC maturation, including NF-κB, mitogen activated protein kinases (MAPKs), and inflammasome signaling, as well as increased type 1 interferon production. Critically, the effects of LTX-315 on DCs the consequent promotion of anti-melanoma immunity depend on the cytosolic signal transducer myeloid differentiation response gene 88 (MyD88). These results cast light on the mechanisms by which LTX-315 induces DC maturation and hence elicits anticancer immunity, with important implications for the use of LTX-315 as an anticancer immunotherapeutic.https://www.frontiersin.org/articles/10.3389/fimmu.2024.1332922/fullantitumor immunitydendritic cellsLTX-315toll-like receptorsMyD88melanoma |
| spellingShingle | Xiao-Qing Li Xiao-Qing Li Takahiro Yamazaki Tianzhen He Md Masud Alam Jia Liu Anna L. Trivett Baldur Sveinbjørnsson Øystein Rekdal Lorenzo Galluzzi Lorenzo Galluzzi Lorenzo Galluzzi Joost J. Oppenheim De Yang LTX-315 triggers anticancer immunity by inducing MyD88-dependent maturation of dendritic cells Frontiers in Immunology antitumor immunity dendritic cells LTX-315 toll-like receptors MyD88 melanoma |
| title | LTX-315 triggers anticancer immunity by inducing MyD88-dependent maturation of dendritic cells |
| title_full | LTX-315 triggers anticancer immunity by inducing MyD88-dependent maturation of dendritic cells |
| title_fullStr | LTX-315 triggers anticancer immunity by inducing MyD88-dependent maturation of dendritic cells |
| title_full_unstemmed | LTX-315 triggers anticancer immunity by inducing MyD88-dependent maturation of dendritic cells |
| title_short | LTX-315 triggers anticancer immunity by inducing MyD88-dependent maturation of dendritic cells |
| title_sort | ltx 315 triggers anticancer immunity by inducing myd88 dependent maturation of dendritic cells |
| topic | antitumor immunity dendritic cells LTX-315 toll-like receptors MyD88 melanoma |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1332922/full |
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