Exosomal PD-L1 derived from hypoxia nasopharyngeal carcinoma cell exacerbates CD8+ T cell suppression by promoting PD-L1 upregulation in macrophages
Abstract Immunotherapy targeting the programmed death ligand-1/programmed cell death protein-1 (PD-L1/PD-1) pathway exhibits limited effectiveness in individuals with recurrent and metastatic nasopharyngeal carcinoma (NPC). Recent studies have noted that hypoxia within the tumor microenvironment (TM...
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2025-05-01
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| Series: | Cancer Immunology, Immunotherapy |
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| Online Access: | https://doi.org/10.1007/s00262-025-04047-7 |
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| author | Xiaofei Yuan Xiong Liu Di Jiang Zijun Zheng Xuemin Ma Shuting Wu Xiangping Li Juan Lu Ming Fu |
| author_facet | Xiaofei Yuan Xiong Liu Di Jiang Zijun Zheng Xuemin Ma Shuting Wu Xiangping Li Juan Lu Ming Fu |
| author_sort | Xiaofei Yuan |
| collection | DOAJ |
| description | Abstract Immunotherapy targeting the programmed death ligand-1/programmed cell death protein-1 (PD-L1/PD-1) pathway exhibits limited effectiveness in individuals with recurrent and metastatic nasopharyngeal carcinoma (NPC). Recent studies have noted that hypoxia within the tumor microenvironment (TME) triggers intricate interplay, termed “hypoxia-induced exosome-mediated communication”, between cancer cells and various immune cells. However, the role of hypoxia in modulating the immunosuppressive environment and its implications on the efficacy of immunotherapy in NPC remains poorly understood. In this study, we found hypoxia inducible factor-1 (HIF-1α) was positively associated with increased PD-L1 levels and decreased CD8+ T cell infiltration, and correlated with a poor prognosis. Mechanistically, we demonstrated that hypoxia regulated the expression of PD-L1 in NPC cells and their exosomes by activating the binding of HIF-1α to the PD-L1 promoter. Meanwhile, using in vitro approaches, we found that macrophages could upregulate their PD-L1 expression through the phagocytosis of exosomal PD-L1 derived from NPC cells. Furthermore, we confirmed that PD-L1+ macrophages could induce CD8+ T cell exhaustion and reduce their proliferation. In conclusion, our study revealed that hypoxia (via HIF-1α) upregulated the expression of PD-L1 in exosomes derived from NPC cells, while macrophages induce the suppression of CD8+ T cells by phagocytosis of exosomal PD-L1. Targeting the PD-L1+ macrophages could potentially serve as a promising approach to augment the effectiveness of immune checkpoint blockade in NPC. |
| format | Article |
| id | doaj-art-70fd0164bdae48b290013e8b60000c1c |
| institution | DOAJ |
| issn | 1432-0851 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Springer |
| record_format | Article |
| series | Cancer Immunology, Immunotherapy |
| spelling | doaj-art-70fd0164bdae48b290013e8b60000c1c2025-08-20T03:21:02ZengSpringerCancer Immunology, Immunotherapy1432-08512025-05-0174711810.1007/s00262-025-04047-7Exosomal PD-L1 derived from hypoxia nasopharyngeal carcinoma cell exacerbates CD8+ T cell suppression by promoting PD-L1 upregulation in macrophagesXiaofei Yuan0Xiong Liu1Di Jiang2Zijun Zheng3Xuemin Ma4Shuting Wu5Xiangping Li6Juan Lu7Ming Fu8Department of Otolaryngology-Head and Neck Surgery, Nanfang Hospital, Southern Medical UniversityDepartment of Otolaryngology-Head and Neck Surgery, Nanfang Hospital, Southern Medical UniversityDepartment of Otolaryngology, The Tenth Affiliated Hospital of Southern Medical University (Dongguan People’s Hospital)Department of Burns, Nanfang Hospital, Southern Medical UniversityDepartment of Otolaryngology-Head and Neck Surgery, Nanfang Hospital, Southern Medical UniversityDepartment of Otolaryngology-Head and Neck Surgery, Nanfang Hospital, Southern Medical UniversityDepartment of Otolaryngology-Head and Neck Surgery, Nanfang Hospital, Southern Medical UniversityDepartment of Otolaryngology-Head and Neck Surgery, Nanfang Hospital, Southern Medical UniversityDepartment of Otolaryngology, The Tenth Affiliated Hospital of Southern Medical University (Dongguan People’s Hospital)Abstract Immunotherapy targeting the programmed death ligand-1/programmed cell death protein-1 (PD-L1/PD-1) pathway exhibits limited effectiveness in individuals with recurrent and metastatic nasopharyngeal carcinoma (NPC). Recent studies have noted that hypoxia within the tumor microenvironment (TME) triggers intricate interplay, termed “hypoxia-induced exosome-mediated communication”, between cancer cells and various immune cells. However, the role of hypoxia in modulating the immunosuppressive environment and its implications on the efficacy of immunotherapy in NPC remains poorly understood. In this study, we found hypoxia inducible factor-1 (HIF-1α) was positively associated with increased PD-L1 levels and decreased CD8+ T cell infiltration, and correlated with a poor prognosis. Mechanistically, we demonstrated that hypoxia regulated the expression of PD-L1 in NPC cells and their exosomes by activating the binding of HIF-1α to the PD-L1 promoter. Meanwhile, using in vitro approaches, we found that macrophages could upregulate their PD-L1 expression through the phagocytosis of exosomal PD-L1 derived from NPC cells. Furthermore, we confirmed that PD-L1+ macrophages could induce CD8+ T cell exhaustion and reduce their proliferation. In conclusion, our study revealed that hypoxia (via HIF-1α) upregulated the expression of PD-L1 in exosomes derived from NPC cells, while macrophages induce the suppression of CD8+ T cells by phagocytosis of exosomal PD-L1. Targeting the PD-L1+ macrophages could potentially serve as a promising approach to augment the effectiveness of immune checkpoint blockade in NPC.https://doi.org/10.1007/s00262-025-04047-7Nasopharyngeal carcinomaHypoxiaPD-L1MacrophageImmune escape |
| spellingShingle | Xiaofei Yuan Xiong Liu Di Jiang Zijun Zheng Xuemin Ma Shuting Wu Xiangping Li Juan Lu Ming Fu Exosomal PD-L1 derived from hypoxia nasopharyngeal carcinoma cell exacerbates CD8+ T cell suppression by promoting PD-L1 upregulation in macrophages Cancer Immunology, Immunotherapy Nasopharyngeal carcinoma Hypoxia PD-L1 Macrophage Immune escape |
| title | Exosomal PD-L1 derived from hypoxia nasopharyngeal carcinoma cell exacerbates CD8+ T cell suppression by promoting PD-L1 upregulation in macrophages |
| title_full | Exosomal PD-L1 derived from hypoxia nasopharyngeal carcinoma cell exacerbates CD8+ T cell suppression by promoting PD-L1 upregulation in macrophages |
| title_fullStr | Exosomal PD-L1 derived from hypoxia nasopharyngeal carcinoma cell exacerbates CD8+ T cell suppression by promoting PD-L1 upregulation in macrophages |
| title_full_unstemmed | Exosomal PD-L1 derived from hypoxia nasopharyngeal carcinoma cell exacerbates CD8+ T cell suppression by promoting PD-L1 upregulation in macrophages |
| title_short | Exosomal PD-L1 derived from hypoxia nasopharyngeal carcinoma cell exacerbates CD8+ T cell suppression by promoting PD-L1 upregulation in macrophages |
| title_sort | exosomal pd l1 derived from hypoxia nasopharyngeal carcinoma cell exacerbates cd8 t cell suppression by promoting pd l1 upregulation in macrophages |
| topic | Nasopharyngeal carcinoma Hypoxia PD-L1 Macrophage Immune escape |
| url | https://doi.org/10.1007/s00262-025-04047-7 |
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