Prostate cancer cells synergistically defend against CD8+ T cells by secreting exosomal PD‐L1
Abstract Background Metastatic castration‐resistant prostate cancer (mCRPC) remains fatal and incurable, despite a variety of treatments that can delay disease progression and prolong life. Immune checkpoint therapy is a promising treatment. However, emerging evidence suggests that exosomal programm...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-08-01
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| Series: | Cancer Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/cam4.6275 |
| _version_ | 1797361234331303936 |
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| author | Dameng Li Xueying Zhou Wenxian Xu Yuxin Chen Chenglong Mu Xinchun Zhao Tao Yang Gang Wang Liang Wei Bo Ma |
| author_facet | Dameng Li Xueying Zhou Wenxian Xu Yuxin Chen Chenglong Mu Xinchun Zhao Tao Yang Gang Wang Liang Wei Bo Ma |
| author_sort | Dameng Li |
| collection | DOAJ |
| description | Abstract Background Metastatic castration‐resistant prostate cancer (mCRPC) remains fatal and incurable, despite a variety of treatments that can delay disease progression and prolong life. Immune checkpoint therapy is a promising treatment. However, emerging evidence suggests that exosomal programmed necrosis ligand 1 (PD‐L1) directly binds to PD‐1 on the surface of T cells in the drain lineage lymph nodes or neutralizes administered PD‐L1 antibodies, resulting in poor response to anti‐PD‐L1 therapy in mCRPC. Materials and Methods Western blotting and immunofluorescence were performed to compare PD‐L1 levels in exosomes derived from different prostate cancer cells. PC3 cells were subcutaneously injected into nude mice, and then ELISA assay was used to detect human specific PD‐L1 in exosomes purified from mouse serum. The function of CD8+ T cells was detected by T cell mediated tumor cell killing assay and FACS analysis. A subcutaneous xenograft model was established using mouse prostate cancer cell RM1, exosomes with or without PD‐L1 were injected every 3 days, and then tumor size and weight were analyzed to evaluate the effect of exosomal PD‐L1. Results Herein, we found that exosomal‐PD‐L1 was taken up by tumor cells expressing low levels of PD‐L1, thereby protecting them from T‐cell killing. Higher levels of PD‐L1 were detected in exosomes derived from the highly malignant prostate cancer PC3 and DU145 cell lines. Moreover, exosomal PD‐L1 was taken up by the PD‐L1‐low‐expressing LNCaP cell line and inhibited the killing function of CD8‐T cells on tumor cells. The growth rate of RM1‐derived subcutaneous tumors was decreased after knockdown of PD‐L1 in tumor cells, whereas the growth rate recovered following exosomal PD‐L1 tail vein injection. Furthermore, in the serum of mice with PCa subcutaneous tumors, PD‐L1 was mainly present on exosomes. Conclusion In summary, tumor cells share PD‐L1 synergistically against T cells through exosomes. Inhibition of exosome secretion or prevention of PD‐L1 sorting into exosomes may improve the therapeutic response of prostate tumors to anti‐PD‐L1 therapy. |
| first_indexed | 2024-03-08T15:50:59Z |
| format | Article |
| id | doaj.art-a527a40de18e463dbefb667bf505e801 |
| institution | Directory Open Access Journal |
| issn | 2045-7634 |
| language | English |
| last_indexed | 2024-03-08T15:50:59Z |
| publishDate | 2023-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | Cancer Medicine |
| spelling | doaj.art-a527a40de18e463dbefb667bf505e8012024-01-09T05:41:08ZengWileyCancer Medicine2045-76342023-08-011215164051641510.1002/cam4.6275Prostate cancer cells synergistically defend against CD8+ T cells by secreting exosomal PD‐L1Dameng Li0Xueying Zhou1Wenxian Xu2Yuxin Chen3Chenglong Mu4Xinchun Zhao5Tao Yang6Gang Wang7Liang Wei8Bo Ma9Cancer Institute Xuzhou Medical University Xuzhou ChinaCancer Institute Xuzhou Medical University Xuzhou ChinaCancer Institute Xuzhou Medical University Xuzhou ChinaCancer Institute Xuzhou Medical University Xuzhou ChinaCancer Institute Xuzhou Medical University Xuzhou ChinaCancer Institute Xuzhou Medical University Xuzhou ChinaCancer Institute Xuzhou Medical University Xuzhou ChinaCancer Institute Xuzhou Medical University Xuzhou ChinaCancer Institute Xuzhou Medical University Xuzhou ChinaCancer Institute Xuzhou Medical University Xuzhou ChinaAbstract Background Metastatic castration‐resistant prostate cancer (mCRPC) remains fatal and incurable, despite a variety of treatments that can delay disease progression and prolong life. Immune checkpoint therapy is a promising treatment. However, emerging evidence suggests that exosomal programmed necrosis ligand 1 (PD‐L1) directly binds to PD‐1 on the surface of T cells in the drain lineage lymph nodes or neutralizes administered PD‐L1 antibodies, resulting in poor response to anti‐PD‐L1 therapy in mCRPC. Materials and Methods Western blotting and immunofluorescence were performed to compare PD‐L1 levels in exosomes derived from different prostate cancer cells. PC3 cells were subcutaneously injected into nude mice, and then ELISA assay was used to detect human specific PD‐L1 in exosomes purified from mouse serum. The function of CD8+ T cells was detected by T cell mediated tumor cell killing assay and FACS analysis. A subcutaneous xenograft model was established using mouse prostate cancer cell RM1, exosomes with or without PD‐L1 were injected every 3 days, and then tumor size and weight were analyzed to evaluate the effect of exosomal PD‐L1. Results Herein, we found that exosomal‐PD‐L1 was taken up by tumor cells expressing low levels of PD‐L1, thereby protecting them from T‐cell killing. Higher levels of PD‐L1 were detected in exosomes derived from the highly malignant prostate cancer PC3 and DU145 cell lines. Moreover, exosomal PD‐L1 was taken up by the PD‐L1‐low‐expressing LNCaP cell line and inhibited the killing function of CD8‐T cells on tumor cells. The growth rate of RM1‐derived subcutaneous tumors was decreased after knockdown of PD‐L1 in tumor cells, whereas the growth rate recovered following exosomal PD‐L1 tail vein injection. Furthermore, in the serum of mice with PCa subcutaneous tumors, PD‐L1 was mainly present on exosomes. Conclusion In summary, tumor cells share PD‐L1 synergistically against T cells through exosomes. Inhibition of exosome secretion or prevention of PD‐L1 sorting into exosomes may improve the therapeutic response of prostate tumors to anti‐PD‐L1 therapy.https://doi.org/10.1002/cam4.6275anti‐PD‐L1 therapyCD8+ T cellsexosomesPD‐L1prostate cancer |
| spellingShingle | Dameng Li Xueying Zhou Wenxian Xu Yuxin Chen Chenglong Mu Xinchun Zhao Tao Yang Gang Wang Liang Wei Bo Ma Prostate cancer cells synergistically defend against CD8+ T cells by secreting exosomal PD‐L1 Cancer Medicine anti‐PD‐L1 therapy CD8+ T cells exosomes PD‐L1 prostate cancer |
| title | Prostate cancer cells synergistically defend against CD8+ T cells by secreting exosomal PD‐L1 |
| title_full | Prostate cancer cells synergistically defend against CD8+ T cells by secreting exosomal PD‐L1 |
| title_fullStr | Prostate cancer cells synergistically defend against CD8+ T cells by secreting exosomal PD‐L1 |
| title_full_unstemmed | Prostate cancer cells synergistically defend against CD8+ T cells by secreting exosomal PD‐L1 |
| title_short | Prostate cancer cells synergistically defend against CD8+ T cells by secreting exosomal PD‐L1 |
| title_sort | prostate cancer cells synergistically defend against cd8 t cells by secreting exosomal pd l1 |
| topic | anti‐PD‐L1 therapy CD8+ T cells exosomes PD‐L1 prostate cancer |
| url | https://doi.org/10.1002/cam4.6275 |
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