LRP11 promotes stem-like T cells via MAPK13-mediated TCF1 phosphorylation, enhancing anti-PD1 immunotherapy
Background Tumor-infiltrating T cells enter an exhausted or dysfunctional state, which limits antitumor immunity. Among exhausted T cells, a subset of cells with features of progenitor or stem-like cells has been identified as TCF1+ CD8+ T cells that respond to immunotherapy. In contrast to the find...
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BMJ Publishing Group
2024-01-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/12/1/e008367.full |
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| author | Zhishui Chen Gang Chen Li Chen Xiangli Zhao Lingjuan Sun Zhibo Ma Xiaosheng Tan Yuhao Tu Jingzeng Wang Peixiang Lan |
| author_facet | Zhishui Chen Gang Chen Li Chen Xiangli Zhao Lingjuan Sun Zhibo Ma Xiaosheng Tan Yuhao Tu Jingzeng Wang Peixiang Lan |
| author_sort | Zhishui Chen |
| collection | DOAJ |
| description | Background Tumor-infiltrating T cells enter an exhausted or dysfunctional state, which limits antitumor immunity. Among exhausted T cells, a subset of cells with features of progenitor or stem-like cells has been identified as TCF1+ CD8+ T cells that respond to immunotherapy. In contrast to the finding that TCF1 controls epigenetic and transcriptional reprogramming in tumor-infiltrating stem-like T cells, little is known about the regulation of TCF1. Emerging data show that elevated body mass index is associated with outcomes of immunotherapy. However, the mechanism has not been clarified.Methods We investigated the proliferation of splenic lymphocytes or CD8+ T cells induced by CD3/CD28 stimulation in vitro. We evaluated the effects of low-density lipoprotein (LDL) and LRP11 inhibitors, as well as MAPK13 inhibitors. Additionally, we used shRNA technology to validate the roles of LRP11 and MAPK13. In an in vivo setting, we employed male C57BL/6J injected with B16 cells or MC38 cells to build a tumor model to assess the effects of LDL and LRP11 inhibitors, LRP11 activators, MAPK13 inhibitors on tumor growth. Flow cytometry was used to measure cell proportions and activation status. Molecular interactions and TCF1 status were examined using Western blotting. Moreover, we employed RNA sequencing to investigate the effects of LDL stimulation and MAPK13 inhibition in CD8+ T cells.Results By using a tumor-bearing mouse model, we found that LDL-induced tumor-infiltrating TCF1+PD1+CD8+ T cells. Using a cell-based chimeric receptor screening system, we showed that LRP11 interacted with LDL and activated TCF1. LRP11 activation enhanced TCF1+PD1+CD8+ T-cell-mediated antitumor immunity, consistent with LRP11 blocking impaired T-cell function. Mechanistically, LRP11 activation induces MAPK13 activation. Then, MAPK13 phosphorylates TCF1, leading to increase of stem-like T cells.Conclusions LRP11-MAPK13-TCF1 enhanced antitumor immunity and induced tumor-infiltrating stem-like T cells. |
| format | Article |
| id | doaj-art-037d05d00d834e63b6c6ee8424c9b959 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2024-01-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-037d05d00d834e63b6c6ee8424c9b9592025-02-12T00:50:10ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262024-01-0112110.1136/jitc-2023-008367LRP11 promotes stem-like T cells via MAPK13-mediated TCF1 phosphorylation, enhancing anti-PD1 immunotherapyZhishui Chen0Gang Chen1Li Chen2Xiangli Zhao3Lingjuan Sun4Zhibo Ma5Xiaosheng Tan6Yuhao Tu7Jingzeng Wang8Peixiang Lan9Institute of Organ Transplantation，Tongji Hospital, Tongji Medical College; Key Laboratory of Organ Transplantation; Ministry of Education, NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Science, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, ChinaInstitute of Organ Transplantation，Tongji Hospital, Tongji Medical College; Key Laboratory of Organ Transplantation; Ministry of Education, NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Science, Huazhong University of Science and Technology, Wuhan, ChinaInstitute of Organ Transplantation，Tongji Hospital, Tongji Medical College; Key Laboratory of Organ Transplantation; Ministry of Education, NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Science, Huazhong University of Science and Technology, Wuhan, ChinaInstitute of Organ Transplantation，Tongji Hospital, Tongji Medical College; Key Laboratory of Organ Transplantation; Ministry of Education, NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Science, Huazhong University of Science and Technology, Wuhan, ChinaInstitute of Organ Transplantation，Tongji Hospital, Tongji Medical College; Key Laboratory of Organ Transplantation; Ministry of Education, NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Science, Huazhong University of Science and Technology, Wuhan, ChinaInstitute of Organ Transplantation，Tongji Hospital, Tongji Medical College; Key Laboratory of Organ Transplantation; Ministry of Education, NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Science, Huazhong University of Science and Technology, Wuhan, ChinaInstitute of Organ Transplantation，Tongji Hospital, Tongji Medical College; Key Laboratory of Organ Transplantation; Ministry of Education, NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Science, Huazhong University of Science and Technology, Wuhan, ChinaInstitute of Organ Transplantation，Tongji Hospital, Tongji Medical College; Key Laboratory of Organ Transplantation; Ministry of Education, NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Science, Huazhong University of Science and Technology, Wuhan, ChinaInstitute of Organ Transplantation，Tongji Hospital, Tongji Medical College; Key Laboratory of Organ Transplantation; Ministry of Education, NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Science, Huazhong University of Science and Technology, Wuhan, ChinaBackground Tumor-infiltrating T cells enter an exhausted or dysfunctional state, which limits antitumor immunity. Among exhausted T cells, a subset of cells with features of progenitor or stem-like cells has been identified as TCF1+ CD8+ T cells that respond to immunotherapy. In contrast to the finding that TCF1 controls epigenetic and transcriptional reprogramming in tumor-infiltrating stem-like T cells, little is known about the regulation of TCF1. Emerging data show that elevated body mass index is associated with outcomes of immunotherapy. However, the mechanism has not been clarified.Methods We investigated the proliferation of splenic lymphocytes or CD8+ T cells induced by CD3/CD28 stimulation in vitro. We evaluated the effects of low-density lipoprotein (LDL) and LRP11 inhibitors, as well as MAPK13 inhibitors. Additionally, we used shRNA technology to validate the roles of LRP11 and MAPK13. In an in vivo setting, we employed male C57BL/6J injected with B16 cells or MC38 cells to build a tumor model to assess the effects of LDL and LRP11 inhibitors, LRP11 activators, MAPK13 inhibitors on tumor growth. Flow cytometry was used to measure cell proportions and activation status. Molecular interactions and TCF1 status were examined using Western blotting. Moreover, we employed RNA sequencing to investigate the effects of LDL stimulation and MAPK13 inhibition in CD8+ T cells.Results By using a tumor-bearing mouse model, we found that LDL-induced tumor-infiltrating TCF1+PD1+CD8+ T cells. Using a cell-based chimeric receptor screening system, we showed that LRP11 interacted with LDL and activated TCF1. LRP11 activation enhanced TCF1+PD1+CD8+ T-cell-mediated antitumor immunity, consistent with LRP11 blocking impaired T-cell function. Mechanistically, LRP11 activation induces MAPK13 activation. Then, MAPK13 phosphorylates TCF1, leading to increase of stem-like T cells.Conclusions LRP11-MAPK13-TCF1 enhanced antitumor immunity and induced tumor-infiltrating stem-like T cells.https://jitc.bmj.com/content/12/1/e008367.full |
| spellingShingle | Zhishui Chen Gang Chen Li Chen Xiangli Zhao Lingjuan Sun Zhibo Ma Xiaosheng Tan Yuhao Tu Jingzeng Wang Peixiang Lan LRP11 promotes stem-like T cells via MAPK13-mediated TCF1 phosphorylation, enhancing anti-PD1 immunotherapy Journal for ImmunoTherapy of Cancer |
| title | LRP11 promotes stem-like T cells via MAPK13-mediated TCF1 phosphorylation, enhancing anti-PD1 immunotherapy |
| title_full | LRP11 promotes stem-like T cells via MAPK13-mediated TCF1 phosphorylation, enhancing anti-PD1 immunotherapy |
| title_fullStr | LRP11 promotes stem-like T cells via MAPK13-mediated TCF1 phosphorylation, enhancing anti-PD1 immunotherapy |
| title_full_unstemmed | LRP11 promotes stem-like T cells via MAPK13-mediated TCF1 phosphorylation, enhancing anti-PD1 immunotherapy |
| title_short | LRP11 promotes stem-like T cells via MAPK13-mediated TCF1 phosphorylation, enhancing anti-PD1 immunotherapy |
| title_sort | lrp11 promotes stem like t cells via mapk13 mediated tcf1 phosphorylation enhancing anti pd1 immunotherapy |
| url | https://jitc.bmj.com/content/12/1/e008367.full |
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