Single-cell and spatial transcriptomics reveal SPP1-CD44 signaling drives primary resistance to immune checkpoint inhibitors in RCC
Abstract Background Immune checkpoint inhibitors (ICIs) are a cornerstone therapy for advanced renal cell carcinoma (RCC). However, significant rates of primary resistance hinder their efficacy, and the underlying mechanisms remain poorly understood. This study aims to unravel the tumor-immune inter...
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BMC
2024-12-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | https://doi.org/10.1186/s12967-024-06018-5 |
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| author | Junfeng Zhang Qingyan Peng Jin Fan Fuzhong Liu Hongbo Chen Xing Bi Shuai Yuan Wei Jiang Ting Pan Kailing Li Sihai Tan Peng Chen |
| author_facet | Junfeng Zhang Qingyan Peng Jin Fan Fuzhong Liu Hongbo Chen Xing Bi Shuai Yuan Wei Jiang Ting Pan Kailing Li Sihai Tan Peng Chen |
| author_sort | Junfeng Zhang |
| collection | DOAJ |
| description | Abstract Background Immune checkpoint inhibitors (ICIs) are a cornerstone therapy for advanced renal cell carcinoma (RCC). However, significant rates of primary resistance hinder their efficacy, and the underlying mechanisms remain poorly understood. This study aims to unravel the tumor-immune interactions and signaling pathways driving primary resistance to ICIs in RCC. Methods We integrated single-cell RNA sequencing, spatial transcriptomics, and clinical sample analysis to investigate the tumor microenvironment and intercellular signaling. Advanced computational methods, including cell–cell communication networks, pseudotime trajectories, and gene set enrichment analysis (GSEA), were employed to uncover the underlying resistance mechanisms. Results Compared to the sensitive group, the primary resistance group exhibited a significant increase in SPP1-CD44 signaling-mediated interactions between tumor cells and immune cells. These interactions disrupted antigen presentation in immune effector cells and suppressed key chemokine and cytokine pathways, thereby impairing effective immune responses. In contrast, the sensitive group showed more active antigen presentation and cytokine signaling, which facilitated stronger immune responses. Furthermore, the interaction between SPP1-secreting tumor cells and CD44-expressing exhausted CD8 + T cells activated the MAPK signaling pathway within CD8 + Tex cells, exacerbating T cell exhaustion and driving the development of ICI resistance in RCC. Conclusion Our findings reveal a potential mechanism by which SPP1-CD44 signaling mediates tumor-immune cell interactions leading to ICI resistance, providing a theoretical basis for targeting and disrupting this signaling to overcome primary resistance in RCC. |
| format | Article |
| id | doaj-art-5f04af898c254866b169fa0f0558c20d |
| institution | Kabale University |
| issn | 1479-5876 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj-art-5f04af898c254866b169fa0f0558c20d2025-01-05T12:44:26ZengBMCJournal of Translational Medicine1479-58762024-12-0122111710.1186/s12967-024-06018-5Single-cell and spatial transcriptomics reveal SPP1-CD44 signaling drives primary resistance to immune checkpoint inhibitors in RCCJunfeng Zhang0Qingyan Peng1Jin Fan2Fuzhong Liu3Hongbo Chen4Xing Bi5Shuai Yuan6Wei Jiang7Ting Pan8Kailing Li9Sihai Tan10Peng Chen11Department of Urology, Xinjiang Medical University Affiliated Cancer HospitalSchool of Nursing, Xinjiang Medical UniversityDepartment of Oncology, The Central Hospital of Enshi Tujia and Miao Autonomous PrefectureCancer Institute, Xinjiang Medical University Affiliated Cancer HospitalDepartment of Urology, The Central Hospital of Enshi Tujia and Miao Autonomous PrefectureDepartment of Urology, Xinjiang Medical University Affiliated Cancer HospitalDepartment of Urology, Xinjiang Medical University Affiliated Cancer HospitalDepartment of Urology, Xinjiang Medical University Affiliated Cancer HospitalDepartment of Urology, Xinjiang Medical University Affiliated Cancer HospitalDepartment of Urology, The Central Hospital of Enshi Tujia and Miao Autonomous PrefectureDepartment of Pediatric, The Central Hospital of Enshi Tujia and Miao Autonomous PrefectureDepartment of Urology, Xinjiang Medical University Affiliated Cancer HospitalAbstract Background Immune checkpoint inhibitors (ICIs) are a cornerstone therapy for advanced renal cell carcinoma (RCC). However, significant rates of primary resistance hinder their efficacy, and the underlying mechanisms remain poorly understood. This study aims to unravel the tumor-immune interactions and signaling pathways driving primary resistance to ICIs in RCC. Methods We integrated single-cell RNA sequencing, spatial transcriptomics, and clinical sample analysis to investigate the tumor microenvironment and intercellular signaling. Advanced computational methods, including cell–cell communication networks, pseudotime trajectories, and gene set enrichment analysis (GSEA), were employed to uncover the underlying resistance mechanisms. Results Compared to the sensitive group, the primary resistance group exhibited a significant increase in SPP1-CD44 signaling-mediated interactions between tumor cells and immune cells. These interactions disrupted antigen presentation in immune effector cells and suppressed key chemokine and cytokine pathways, thereby impairing effective immune responses. In contrast, the sensitive group showed more active antigen presentation and cytokine signaling, which facilitated stronger immune responses. Furthermore, the interaction between SPP1-secreting tumor cells and CD44-expressing exhausted CD8 + T cells activated the MAPK signaling pathway within CD8 + Tex cells, exacerbating T cell exhaustion and driving the development of ICI resistance in RCC. Conclusion Our findings reveal a potential mechanism by which SPP1-CD44 signaling mediates tumor-immune cell interactions leading to ICI resistance, providing a theoretical basis for targeting and disrupting this signaling to overcome primary resistance in RCC.https://doi.org/10.1186/s12967-024-06018-5Advanced renal cell carcinomaPrimary resistanceSPP1-CD44 signalingCell–cell communicationMAPK signaling |
| spellingShingle | Junfeng Zhang Qingyan Peng Jin Fan Fuzhong Liu Hongbo Chen Xing Bi Shuai Yuan Wei Jiang Ting Pan Kailing Li Sihai Tan Peng Chen Single-cell and spatial transcriptomics reveal SPP1-CD44 signaling drives primary resistance to immune checkpoint inhibitors in RCC Journal of Translational Medicine Advanced renal cell carcinoma Primary resistance SPP1-CD44 signaling Cell–cell communication MAPK signaling |
| title | Single-cell and spatial transcriptomics reveal SPP1-CD44 signaling drives primary resistance to immune checkpoint inhibitors in RCC |
| title_full | Single-cell and spatial transcriptomics reveal SPP1-CD44 signaling drives primary resistance to immune checkpoint inhibitors in RCC |
| title_fullStr | Single-cell and spatial transcriptomics reveal SPP1-CD44 signaling drives primary resistance to immune checkpoint inhibitors in RCC |
| title_full_unstemmed | Single-cell and spatial transcriptomics reveal SPP1-CD44 signaling drives primary resistance to immune checkpoint inhibitors in RCC |
| title_short | Single-cell and spatial transcriptomics reveal SPP1-CD44 signaling drives primary resistance to immune checkpoint inhibitors in RCC |
| title_sort | single cell and spatial transcriptomics reveal spp1 cd44 signaling drives primary resistance to immune checkpoint inhibitors in rcc |
| topic | Advanced renal cell carcinoma Primary resistance SPP1-CD44 signaling Cell–cell communication MAPK signaling |
| url | https://doi.org/10.1186/s12967-024-06018-5 |
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