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PD-L1表达与TILs浸润分型预测食管鳞癌免疫联合化疗疗效的临床研究
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Abstract:
目的：评估PD-L1表达(CPS)和TILs密度对ESCC免疫联合化疗疗效的预测能力，验证TIME分型体系，探索其临床转化潜力。方法：回顾性分析2017年1月至2024年12月青岛大学附属医院收治的238例初治ESCC患者，均接受PD-1/PD-L1抑制剂联合化疗。通过免疫组化检测PD-L1表达(CPS)和TILs密度，基于PD-L1 (CPS ≥ 10)和TILs (≥20%)将TIME分为四型(PD-L1+/TIL+、PD-L1+/TIL？、PD-L1？/TIL+、PD-L1？/TIL？)。采用Fisher-Freeman-Halton检验等统计学方法评估各型ORR差异，并用Kaplan-Meier法及Log-rank检验分析生存数据。结果：PD-L1阳性(CPS ≥ 10)和TILs高浸润(≥20%)患者ORR更高(PD-L1+ vs. PD-L1？: 34.9% vs. 20.8%, P = 0.030; TIL+ vs. TIL？: 42.7% vs. 7.4%, P < 0.001)。II型(PD-L1+/TIL+) ORR最高(44.55%)，显著优于其他亚型(vs. IV型：P < 0.001；vs. III型：P = 0.017；vs. I型：P = 0.025)；I型(PD-L1？/TIL？) ORR最低(12.50%)。生存分析显示，II型中位OS (37.4个月)和PFS (23.1个月)显著优于I型和IV型(Log-rank P < 0.001)。结论：TIME分型可有效预测ESCC免疫联合化疗的疗效和生存结局。II型为理想获益人群，I型及IV型需探索逆转免疫抑制的策略。
Objective: To assess the predictive value of PD-L1 expression (CPS) and TILs density for ICI-chemotherapy efficacy in ESCC patients and validate the TIME classification system. Methods: Retrospective analysis of 238 treatment-na？ve ESCC patients receiving PD-1/PD-L1 inhibitors combined with chemotherapy from January 2017 to December 2024. PD-L1 (CPS) and TILs density were evaluated by immunohistochemistry. TIME was classified into four subtypes based on PD-L1 (CPS ≥ 10) and TILs (≥20%). ORR differences were assessed using Fisher-Freeman-Halton test, and survival data were analyzed using Kaplan-Meier and Log-rank tests. Results: PD-L1 positivity (CPS ≥ 10) and high TILs infiltration (≥20%) were associated with higher ORR (PD-L1+ vs. PD-L1？: 34.9% vs. 20.8%, P = 0.030; TIL+ vs. TIL？: 42.7% vs. 7.4%, P < 0.001). Type II (PD-L1+/TIL+) had the highest ORR (44.55%) which was significantly better than other subtypes (vs. Type IV: P < 0.001; vs. Type III: P = 0.017; vs. Type I: P = 0.025); Type I (PD-L1？/TIL？) had the lowest ORR (12.50%). Survival analysis showed that Type II had significantly longer median OS (37.4 months) and PFS (23.1 months) compared with Type I and Type IV (Log-rank P < 0.001). Conclusion: TIME classification effectively predicts the efficacy and survival outcomes of ICI-chemotherapy in ESCC patients. Type II
| [1] | Sung, H., Ferlay, J., Siegel, R.L., Laversanne, M., Soerjomataram, I., Jemal, A., et al. (2021) Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: A Cancer Journal for Clinicians, 71, 209-249. https://doi.org/10.3322/caac.21660 |
| [2] | Abnet, C.C., Arnold, M. and Wei, W. (2018) Epidemiology of Esophageal Squamous Cell Carcinoma. Gastroenterology, 154, 360-373. https://doi.org/10.1053/j.gastro.2017.08.023 |
| [3] | Yang, H., Wang, F., Hallemeier, C.L., Lerut, T. and Fu, J. (2024) Oesophageal Cancer. The Lancet, 404, 1991-2005. https://doi.org/10.1016/s0140-6736(24)02226-8 |
| [4] | Zhang, Y., Chen, H., Mo, H., Zhao, N., Sun, X., Liu, B., et al. (2025) Distinct Cellular Mechanisms Underlie Chemotherapies and PD-L1 Blockade Combinations in Triple-Negative Breast Cancer. Cancer Cell, 43, 446-463.e7. https://doi.org/10.1016/j.ccell.2025.01.007 |
| [5] | Tang, Q., Chen, Y., Li, X., Long, S., Shi, Y., Yu, Y., et al. (2022) The Role of PD-1/PD-L1 and Application of Immune-Checkpoint Inhibitors in Human Cancers. Frontiers in Immunology, 13, Article 964442. https://doi.org/10.3389/fimmu.2022.964442 |
| [6] | Kojima, T., Shah, M.A., Muro, K., Francois, E., Adenis, A., Hsu, C., et al. (2020) Randomized Phase III KEYNOTE-181 Study of Pembrolizumab versus Chemotherapy in Advanced Esophageal Cancer. Journal of Clinical Oncology, 38, 4138-4148. https://doi.org/10.1200/jco.20.01888 |
| [7] | 中华人民共和国国家卫生健康委员会医政医管局. 食管癌诊疗指南(2022年版) [J]. 中华消化外科杂志, 2022, 21(10): 1247-1268. |
| [8] | Kim, T.K., Vandsemb, E.N., Herbst, R.S. and Chen, L. (2022) Adaptive Immune Resistance at the Tumour Site: Mechanisms and Therapeutic Opportunities. Nature Reviews Drug Discovery, 21, 529-540. https://doi.org/10.1038/s41573-022-00493-5 |
| [9] | Sun, J., Shen, L., Shah, M.A., Enzinger, P., Adenis, A., Doi, T., et al. (2021) Pembrolizumab Plus Chemotherapy versus Chemotherapy Alone for First-Line Treatment of Advanced Oesophageal Cancer (KEYNOTE-590): A Randomised, Placebo-Controlled, Phase 3 Study. The Lancet, 398, 759-771. https://doi.org/10.1016/s0140-6736(21)01234-4 |
| [10] | Ayers, M., Lunceford, J., Nebozhyn, M., Murphy, E., Loboda, A., Kaufman, D.R., et al. (2017) IFN-γ-Related mRNA Profile Predicts Clinical Response to PD-1 Blockade. Journal of Clinical Investigation, 127, 2930-2940. https://doi.org/10.1172/jci91190 |
| [11] | Galluzzi, L., Humeau, J., Buqué, A., Zitvogel, L. and Kroemer, G. (2020) Immunostimulation with Chemotherapy in the Era of Immune Checkpoint Inhibitors. Nature Reviews Clinical Oncology, 17, 725-741. https://doi.org/10.1038/s41571-020-0413-z |
| [12] | Galon, J. and Bruni, D. (2019) Approaches to Treat Immune Hot, Altered and Cold Tumours with Combination Immunotherapies. Nature Reviews Drug Discovery, 18, 197-218. https://doi.org/10.1038/s41573-018-0007-y |
| [13] | Garcia-Diaz, A., Shin, D.S., Moreno, B.H., Saco, J., Escuin-Ordinas, H., Rodriguez, G.A., et al. (2017) Interferon Receptor Signaling Pathways Regulating PD-L1 and PD-L2 Expression. Cell Reports, 19, 1189-1201. https://doi.org/10.1016/j.celrep.2017.04.031 |
| [14] | Doki, Y., Ajani, J.A., Kato, K., Xu, J., Wyrwicz, L., Motoyama, S., et al. (2022) Nivolumab Combination Therapy in Advanced Esophageal Squamous-Cell Carcinoma. New England Journal of Medicine, 386, 449-462. https://doi.org/10.1056/nejmoa2111380 |
| [15] | Xu, J., Jiang, H., Pan, Y., Gu, K., Cang, S., Han, L., et al. (2023) Sintilimab Plus Chemotherapy for Unresectable Gastric or Gastroesophageal Junction Cancer: The ORIENT-16 Randomized Clinical Trial. JAMA, 330, 2064-2074. https://doi.org/10.1001/jama.2023.19918 |
| [16] | Chen, D.S. and Mellman, I. (2017) Elements of Cancer Immunity and the Cancer-Immune Set Point. Nature, 541, 321-330. https://doi.org/10.1038/nature21349 |
| [17] | Taube, J.M., Klein, A., Brahmer, J.R., Xu, H., Pan, X., Kim, J.H., et al. (2014) Association of PD-1, PD-1 Ligands, and Other Features of the Tumor Immune Microenvironment with Response to Anti-PD-1 Therapy. Clinical Cancer Research, 20, 5064-5074. https://doi.org/10.1158/1078-0432.ccr-13-3271 |
| [18] | Tumeh, P.C., Harview, C.L., Yearley, J.H., Shintaku, I.P., Taylor, E.J.M., Robert, L., et al. (2014) PD-1 Blockade Induces Responses by Inhibiting Adaptive Immune Resistance. Nature, 515, 568-571. https://doi.org/10.1038/nature13954 |
| [19] | Farrag, M.S., Abdelwahab, K., Farrag, N.S., Elrefaie, W.E. and Emarah, Z. (2021) Programmed Death Ligand-1 and CD8 Tumor-Infiltrating Lymphocytes (TILs) as Prognostic Predictors in Ovarian High-Grade Serous Carcinoma (HGSC). Journal of the Egyptian National Cancer Institute, 33, Article No. 16. https://doi.org/10.1186/s43046-021-00073-5 |
| [20] | Mantovani, A., Marchesi, F., Malesci, A., Laghi, L. and Allavena, P. (2017) Tumour-associated Macrophages as Treatment Targets in Oncology. Nature Reviews Clinical Oncology, 14, 399-416. https://doi.org/10.1038/nrclinonc.2016.217 |
| [21] | Chau, I. (2017) Clinical Development of PD-1/PD-L1 Immunotherapy for Gastrointestinal Cancers: Facts and Hopes. Clinical Cancer Research, 23, 6002-6011. https://doi.org/10.1158/1078-0432.ccr-17-0020 |
| [22] | Chen, Z., Zhou, L., Liu, L., Hou, Y., Xiong, M., Yang, Y., et al. (2020) Single-Cell RNA Sequencing Highlights the Role of Inflammatory Cancer-Associated Fibroblasts in Bladder Urothelial Carcinoma. Nature Communications, 11, Article No. 5077. https://doi.org/10.1038/s41467-020-18916-5 |
| [23] | Ma, F., Liu, X., Zhang, Y., Tao, Y., Zhao, L., Abusalamah, H., et al. (2025) Tumor Extracellular Vesicle-Derived PD-L1 Promotes T Cell Senescence through Lipid Metabolism Reprogramming. Science Translational Medicine, 17, eadm7269. https://doi.org/10.1126/scitranslmed.adm7269 |
| [24] | Wei, S.C., Duffy, C.R. and Allison, J.P. (2018) Fundamental Mechanisms of Immune Checkpoint Blockade Therapy. Cancer Discovery, 8, 1069-1086. https://doi.org/10.1158/2159-8290.cd-18-0367 |
| [25] | Zhang, Y. and Chen, L. (2016) Classification of Advanced Human Cancers Based on Tumor Immunity in the Microenvironment (TIME) for Cancer Immunotherapy. JAMA Oncology, 2, 1403-1404. https://doi.org/10.1001/jamaoncol.2016.2450 |
| [26] | Bagaev, A., Kotlov, N., Nomie, K., Svekolkin, V., Gafurov, A., Isaeva, O., et al. (2021) Conserved Pan-Cancer Microenvironment Subtypes Predict Response to Immunotherapy. Cancer Cell, 39, 845-865.e7. https://doi.org/10.1016/j.ccell.2021.04.014 |
| [27] | Teng, M.W.L., Ngiow, S.F., Ribas, A. and Smyth, M.J. (2015) Classifying Cancers Based on T-Cell Infiltration and Pd-l1. Cancer Research, 75, 2139-2145. https://doi.org/10.1158/0008-5472.can-15-0255 |
| [28] | Binnewies, M., Roberts, E.W., Kersten, K., Chan, V., Fearon, D.F., Merad, M., et al. (2018) Understanding the Tumor Immune Microenvironment (TIME) for Effective Therapy. Nature Medicine, 24, 541-550. https://doi.org/10.1038/s41591-018-0014-x |
| [29] | Sun, D., Liu, J., Zhou, H., Shi, M., Sun, J., Zhao, S., et al. (2023) Classification of Tumor Immune Microenvironment According to Programmed Death-Ligand 1 Expression and Immune Infiltration Predicts Response to Immunotherapy Plus Chemotherapy in Advanced Patients with NSCLC. Journal of Thoracic Oncology, 18, 869-881. https://doi.org/10.1016/j.jtho.2023.03.012 |
| [30] | Jiao, R., Luo, H., Xu, W. and Ge, H. (2019) immune Checkpoint Inhibitors in Esophageal Squamous Cell Carcinoma: Progress and Opportunities. OncoTargets and Therapy, 12, 6023-6032. https://doi.org/10.2147/ott.s214579 |
