Oncolytic peptide LTX-315 induces anti-pancreatic cancer immunity by targeting the ATP11B-PD-L1 axis
Background LTX-315 is an oncolytic peptide deriving from bovine lactoferrin, with the ability to induce cancer immunogenic cell death. However, the mechanism used by LTX-315 to trigger the antitumor immune response is still poorly understood. The expression of programmed cell death ligand 1 (PD-L1)...
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| Language: | English |
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BMJ Publishing Group
2022-03-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/10/3/e004129.full |
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| author | Meng Wang Xing Huang Tingbo Liang Tianyu Tang Gang Zhang Minghao Lu Zhengtao Hong Junming Huang Xiao Zhi |
| author_facet | Meng Wang Xing Huang Tingbo Liang Tianyu Tang Gang Zhang Minghao Lu Zhengtao Hong Junming Huang Xiao Zhi |
| author_sort | Meng Wang |
| collection | DOAJ |
| description | Background LTX-315 is an oncolytic peptide deriving from bovine lactoferrin, with the ability to induce cancer immunogenic cell death. However, the mechanism used by LTX-315 to trigger the antitumor immune response is still poorly understood. The expression of programmed cell death ligand 1 (PD-L1) largely determines the efficacy and effectiveness of cancer immunotherapies targeting this specific immune checkpoint. This study aimed to demonstrate the potential effect and mechanism of LTX-315 in PD-L1 inhibition-induced anti-pancreatic cancer immunity.Methods Both immunodeficient and immunocompetent mouse models were used to evaluate the therapeutic efficacy of monotherapy and combination therapy. Flow cytometry and immunohistochemistry were used to assess the immune microenvironment. Multiomic analysis was used to identify the potential target and down-streaming signaling pathway. Both in-house tissue microarray and open accessed The Cancer Genome Atlas data sets were used to evaluate the clinical relevance in pancreatic cancer prognosis.Results LTX-315 treatment inhibited PD-L1 expression and enhanced lymphocyte infiltration in pancreatic tumors. ATP11B was identified as a potential target of LTX-315 and a critical regulator in maintaining PD-L1 expression in pancreatic cancer cells. As regards the mechanism, ATP11B interacted with PD-L1 in a CKLF-like MARVEL transmembrane domain containing 6 (CMTM6)-dependent manner. The depletion of ATP11B promoted CMTM6-mediated lysosomal degradation of PD-L1, thus reactivating the immune microenvironment and inducing an antitumor immune response. The significant correlation among ATP11B, CMTM6, and PD-L1 was confirmed in clinical samples of pancreatic cancer.Conclusions LTX-315 was first identified as a peptide drug inducing PD-L1 downregulation via ATP11B. Therefore, LTX-315, or the development of ATP11B-targeting drugs, might improve the efficacy of cancer immunotherapy. |
| format | Article |
| id | doaj-art-6de3c324d609435694a81a5426c2d876 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2022-03-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-6de3c324d609435694a81a5426c2d8762025-02-09T07:05:09ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262022-03-0110310.1136/jitc-2021-004129Oncolytic peptide LTX-315 induces anti-pancreatic cancer immunity by targeting the ATP11B-PD-L1 axisMeng Wang0Xing Huang1Tingbo Liang2Tianyu Tang3Gang Zhang4Minghao Lu5Zhengtao Hong6Junming Huang7Xiao Zhi8Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People`s Republic of ChinaZhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People`s Republic of ChinaDepartment of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, ChinaThe Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, People`s Republic of ChinaZhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People`s Republic of ChinaCancer Center, Zhejiang University, Hangzhou, People`s Republic of ChinaDepartment of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People`s Republic of ChinaZhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People`s Republic of ChinaDepartment of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People`s Republic of ChinaBackground LTX-315 is an oncolytic peptide deriving from bovine lactoferrin, with the ability to induce cancer immunogenic cell death. However, the mechanism used by LTX-315 to trigger the antitumor immune response is still poorly understood. The expression of programmed cell death ligand 1 (PD-L1) largely determines the efficacy and effectiveness of cancer immunotherapies targeting this specific immune checkpoint. This study aimed to demonstrate the potential effect and mechanism of LTX-315 in PD-L1 inhibition-induced anti-pancreatic cancer immunity.Methods Both immunodeficient and immunocompetent mouse models were used to evaluate the therapeutic efficacy of monotherapy and combination therapy. Flow cytometry and immunohistochemistry were used to assess the immune microenvironment. Multiomic analysis was used to identify the potential target and down-streaming signaling pathway. Both in-house tissue microarray and open accessed The Cancer Genome Atlas data sets were used to evaluate the clinical relevance in pancreatic cancer prognosis.Results LTX-315 treatment inhibited PD-L1 expression and enhanced lymphocyte infiltration in pancreatic tumors. ATP11B was identified as a potential target of LTX-315 and a critical regulator in maintaining PD-L1 expression in pancreatic cancer cells. As regards the mechanism, ATP11B interacted with PD-L1 in a CKLF-like MARVEL transmembrane domain containing 6 (CMTM6)-dependent manner. The depletion of ATP11B promoted CMTM6-mediated lysosomal degradation of PD-L1, thus reactivating the immune microenvironment and inducing an antitumor immune response. The significant correlation among ATP11B, CMTM6, and PD-L1 was confirmed in clinical samples of pancreatic cancer.Conclusions LTX-315 was first identified as a peptide drug inducing PD-L1 downregulation via ATP11B. Therefore, LTX-315, or the development of ATP11B-targeting drugs, might improve the efficacy of cancer immunotherapy.https://jitc.bmj.com/content/10/3/e004129.full |
| spellingShingle | Meng Wang Xing Huang Tingbo Liang Tianyu Tang Gang Zhang Minghao Lu Zhengtao Hong Junming Huang Xiao Zhi Oncolytic peptide LTX-315 induces anti-pancreatic cancer immunity by targeting the ATP11B-PD-L1 axis Journal for ImmunoTherapy of Cancer |
| title | Oncolytic peptide LTX-315 induces anti-pancreatic cancer immunity by targeting the ATP11B-PD-L1 axis |
| title_full | Oncolytic peptide LTX-315 induces anti-pancreatic cancer immunity by targeting the ATP11B-PD-L1 axis |
| title_fullStr | Oncolytic peptide LTX-315 induces anti-pancreatic cancer immunity by targeting the ATP11B-PD-L1 axis |
| title_full_unstemmed | Oncolytic peptide LTX-315 induces anti-pancreatic cancer immunity by targeting the ATP11B-PD-L1 axis |
| title_short | Oncolytic peptide LTX-315 induces anti-pancreatic cancer immunity by targeting the ATP11B-PD-L1 axis |
| title_sort | oncolytic peptide ltx 315 induces anti pancreatic cancer immunity by targeting the atp11b pd l1 axis |
| url | https://jitc.bmj.com/content/10/3/e004129.full |
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