The Spatial Proximity of CD8<sup>+</sup> FoxP3<sup>+</sup>PD-1<sup>+</sup> Cells to Tumor Cells: A More Accurate Predictor of Immunotherapy Outcomes in Advanced Non-Small-Cell Lung Cancer
Background: To optimize precision immunotherapy for advanced NSCLC, comprehensive tumor immune microenvironment (TIME) characterization is crucial for efficacy prediction. Methods: Pretreatment tumor samples from 46 advanced NSCLC patients treated with PD-1/PD-L1 inhibitors were analyzed. The subreg...
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MDPI AG
2025-04-01
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| Series: | Current Oncology |
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| Online Access: | https://www.mdpi.com/1718-7729/32/5/262 |
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| author | Zijuan Hu Zhihuang Hu Keji Chen Huixia Huang Xinyang Zhong Yaxian Wang Jiayu Chen Xuefeng He Di Shi Yupeng Zeng Jiwei Li Xiaoyan Zhou Ping Wei |
| author_facet | Zijuan Hu Zhihuang Hu Keji Chen Huixia Huang Xinyang Zhong Yaxian Wang Jiayu Chen Xuefeng He Di Shi Yupeng Zeng Jiwei Li Xiaoyan Zhou Ping Wei |
| author_sort | Zijuan Hu |
| collection | DOAJ |
| description | Background: To optimize precision immunotherapy for advanced NSCLC, comprehensive tumor immune microenvironment (TIME) characterization is crucial for efficacy prediction. Methods: Pretreatment tumor samples from 46 advanced NSCLC patients treated with PD-1/PD-L1 inhibitors were analyzed. The subregional abundance and spatial proximity scores of TIME cell subpopulations in 27 samples were assessed via multiplex immunohistochemistry (mIHC) targeting pan-CK, CD163, CD8, FoxP3, PD-1, and PD-L1. Correlations between the TIME features, clinicopathologic factors, treatment response, and prognosis were evaluated. Results: CD8<sup>+</sup>FoxP3<sup>+</sup> cells were identified in NSCLC tissues, predominantly expressing PD-1/PD-L1. The PD-L1 TPS subgroups showed significant immune cell density/proximity differences, but CD8<sup>+</sup>FoxP3<sup>+</sup>PD-1<sup>+</sup> infiltration was PD-L1 TPS-independent. Responders had higher CD8<sup>+</sup>FoxP3<sup>+</sup>PD-1<sup>high</sup> density (<i>p</i> = 0.0497) and proximity scores (<i>p</i> = 0.0099) than non-responders. The CD8<sup>+</sup>FoxP3<sup>+</sup>PD-1<sup>+</sup> presence and tumor proximity were essential for favorable outcomes. In low-PD-L1 TPS patients, the CD8<sup>+</sup>FoxP3<sup>+</sup>PD-1<sup>+</sup> abundance and proximity scores strongly predicted the response (AUC: 0.79 and 0.75 vs. PD-L1 TPS AUC = 0.58). A survival analysis linked the presence and proximity score of CD8<sup>+</sup>FoxP3<sup>+</sup>PD-1<sup>+</sup> cells to prolonged overall survival (OS) and progression-free survival (PFS). Notably, a low proximity score of CD8<sup>+</sup>FoxP3<sup>+</sup>PD-1<sup>+</sup> cells emerged as an independent risk factor for a shorter PFS (HR = 6.16, 95% CI: 2.12–17.93, <i>p</i> = 0.001). Conclusion: The CD8<sup>+</sup>FoxP3<sup>+</sup>PD-1<sup>+</sup> spatial proximity to tumor cells robustly predicts improved immunotherapy outcomes in advanced NSCLC. |
| format | Article |
| id | doaj-art-7f5ee6805c3243d6a3c59e6f35c4c0ff |
| institution | OA Journals |
| issn | 1198-0052 1718-7729 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Current Oncology |
| spelling | doaj-art-7f5ee6805c3243d6a3c59e6f35c4c0ff2025-08-20T01:56:23ZengMDPI AGCurrent Oncology1198-00521718-77292025-04-0132526210.3390/curroncol32050262The Spatial Proximity of CD8<sup>+</sup> FoxP3<sup>+</sup>PD-1<sup>+</sup> Cells to Tumor Cells: A More Accurate Predictor of Immunotherapy Outcomes in Advanced Non-Small-Cell Lung CancerZijuan Hu0Zhihuang Hu1Keji Chen2Huixia Huang3Xinyang Zhong4Yaxian Wang5Jiayu Chen6Xuefeng He7Di Shi8Yupeng Zeng9Jiwei Li10Xiaoyan Zhou11Ping Wei12Cancer Institute, Fudan University Shanghai Cancer Center, 270 Dong’an Road, Shanghai 200032, ChinaDepartment of Oncology, Shanghai Medical College, Fudan University, 270 Dong’an Road, Shanghai 200032, ChinaCancer Institute, Fudan University Shanghai Cancer Center, 270 Dong’an Road, Shanghai 200032, ChinaCancer Institute, Fudan University Shanghai Cancer Center, 270 Dong’an Road, Shanghai 200032, ChinaDepartment of Oncology, Shanghai Medical College, Fudan University, 270 Dong’an Road, Shanghai 200032, ChinaDepartment of Oncology, Shanghai Medical College, Fudan University, 270 Dong’an Road, Shanghai 200032, ChinaDepartment of Oncology, Shanghai Medical College, Fudan University, 270 Dong’an Road, Shanghai 200032, ChinaDepartment of Oncology, Shanghai Medical College, Fudan University, 270 Dong’an Road, Shanghai 200032, ChinaDepartment of Oncology, Shanghai Medical College, Fudan University, 270 Dong’an Road, Shanghai 200032, ChinaDepartment of Oncology, Shanghai Medical College, Fudan University, 270 Dong’an Road, Shanghai 200032, ChinaDepartment of Oncology, The Second Xiangya Hospital, Central South University, Changsha 410011, ChinaDepartment of Oncology, Shanghai Medical College, Fudan University, 270 Dong’an Road, Shanghai 200032, ChinaCancer Institute, Fudan University Shanghai Cancer Center, 270 Dong’an Road, Shanghai 200032, ChinaBackground: To optimize precision immunotherapy for advanced NSCLC, comprehensive tumor immune microenvironment (TIME) characterization is crucial for efficacy prediction. Methods: Pretreatment tumor samples from 46 advanced NSCLC patients treated with PD-1/PD-L1 inhibitors were analyzed. The subregional abundance and spatial proximity scores of TIME cell subpopulations in 27 samples were assessed via multiplex immunohistochemistry (mIHC) targeting pan-CK, CD163, CD8, FoxP3, PD-1, and PD-L1. Correlations between the TIME features, clinicopathologic factors, treatment response, and prognosis were evaluated. Results: CD8<sup>+</sup>FoxP3<sup>+</sup> cells were identified in NSCLC tissues, predominantly expressing PD-1/PD-L1. The PD-L1 TPS subgroups showed significant immune cell density/proximity differences, but CD8<sup>+</sup>FoxP3<sup>+</sup>PD-1<sup>+</sup> infiltration was PD-L1 TPS-independent. Responders had higher CD8<sup>+</sup>FoxP3<sup>+</sup>PD-1<sup>high</sup> density (<i>p</i> = 0.0497) and proximity scores (<i>p</i> = 0.0099) than non-responders. The CD8<sup>+</sup>FoxP3<sup>+</sup>PD-1<sup>+</sup> presence and tumor proximity were essential for favorable outcomes. In low-PD-L1 TPS patients, the CD8<sup>+</sup>FoxP3<sup>+</sup>PD-1<sup>+</sup> abundance and proximity scores strongly predicted the response (AUC: 0.79 and 0.75 vs. PD-L1 TPS AUC = 0.58). A survival analysis linked the presence and proximity score of CD8<sup>+</sup>FoxP3<sup>+</sup>PD-1<sup>+</sup> cells to prolonged overall survival (OS) and progression-free survival (PFS). Notably, a low proximity score of CD8<sup>+</sup>FoxP3<sup>+</sup>PD-1<sup>+</sup> cells emerged as an independent risk factor for a shorter PFS (HR = 6.16, 95% CI: 2.12–17.93, <i>p</i> = 0.001). Conclusion: The CD8<sup>+</sup>FoxP3<sup>+</sup>PD-1<sup>+</sup> spatial proximity to tumor cells robustly predicts improved immunotherapy outcomes in advanced NSCLC.https://www.mdpi.com/1718-7729/32/5/262CD8<sup>+</sup>FoxP3<sup>+</sup>PD-1<sup>+</sup> cellsspatial proximityPD-1/PD-L1 blockadetherapeutic outcomesadvanced non-small-cell lung cancer |
| spellingShingle | Zijuan Hu Zhihuang Hu Keji Chen Huixia Huang Xinyang Zhong Yaxian Wang Jiayu Chen Xuefeng He Di Shi Yupeng Zeng Jiwei Li Xiaoyan Zhou Ping Wei The Spatial Proximity of CD8<sup>+</sup> FoxP3<sup>+</sup>PD-1<sup>+</sup> Cells to Tumor Cells: A More Accurate Predictor of Immunotherapy Outcomes in Advanced Non-Small-Cell Lung Cancer Current Oncology CD8<sup>+</sup>FoxP3<sup>+</sup>PD-1<sup>+</sup> cells spatial proximity PD-1/PD-L1 blockade therapeutic outcomes advanced non-small-cell lung cancer |
| title | The Spatial Proximity of CD8<sup>+</sup> FoxP3<sup>+</sup>PD-1<sup>+</sup> Cells to Tumor Cells: A More Accurate Predictor of Immunotherapy Outcomes in Advanced Non-Small-Cell Lung Cancer |
| title_full | The Spatial Proximity of CD8<sup>+</sup> FoxP3<sup>+</sup>PD-1<sup>+</sup> Cells to Tumor Cells: A More Accurate Predictor of Immunotherapy Outcomes in Advanced Non-Small-Cell Lung Cancer |
| title_fullStr | The Spatial Proximity of CD8<sup>+</sup> FoxP3<sup>+</sup>PD-1<sup>+</sup> Cells to Tumor Cells: A More Accurate Predictor of Immunotherapy Outcomes in Advanced Non-Small-Cell Lung Cancer |
| title_full_unstemmed | The Spatial Proximity of CD8<sup>+</sup> FoxP3<sup>+</sup>PD-1<sup>+</sup> Cells to Tumor Cells: A More Accurate Predictor of Immunotherapy Outcomes in Advanced Non-Small-Cell Lung Cancer |
| title_short | The Spatial Proximity of CD8<sup>+</sup> FoxP3<sup>+</sup>PD-1<sup>+</sup> Cells to Tumor Cells: A More Accurate Predictor of Immunotherapy Outcomes in Advanced Non-Small-Cell Lung Cancer |
| title_sort | spatial proximity of cd8 sup sup foxp3 sup sup pd 1 sup sup cells to tumor cells a more accurate predictor of immunotherapy outcomes in advanced non small cell lung cancer |
| topic | CD8<sup>+</sup>FoxP3<sup>+</sup>PD-1<sup>+</sup> cells spatial proximity PD-1/PD-L1 blockade therapeutic outcomes advanced non-small-cell lung cancer |
| url | https://www.mdpi.com/1718-7729/32/5/262 |
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