非小细胞肺癌免疫治疗疗效预测标志物研究进展
Research Progress in Prognostic Markers of Immunotherapy for Non-Small Cell Lung Cancer
DOI: 10.12677/ACM.2023.131041, PDF,    科研立项经费支持
作者: 张科宇, 孙尚莹, 高芝兰：西安医学院，陕西 西安；李索妮, 郑 琪, 赵 征*：西安交通大学医学院附属陕西省肿瘤医院，陕西 西安
关键词: 非小细胞肺癌；免疫治疗；预测标志物；Non-Small Cell Lung Cancer； Immunotherapy； Predictors
摘要: 近年来免疫检查点抑制剂(immune checkpoint inhibitor, ICIs)在非小细胞肺癌(non-small cell lung cancer, NSCLC)的治疗中取得了巨大的进展，NSCLC的免疫治疗已成为继手术、化疗、放疗后的标准治疗方法之一，但只有部分NSCLC患者能从ICIs治疗中获益，因此，迫切需要探索出能够预测ICIs疗效的生物标志物，为临床优势人群的筛选提供依据。肿瘤程序性死亡配体-1 (programmed cell death ligand 1, PD-L1)是免疫治疗中最早进行探索的指标，对于免疫治疗的疗效展现出一定的预测作用，但具有一定的局限性，其他生物标志物也展现出一定的预测作用，例如肿瘤突变负荷(tumor muta-tion burden, TMB)、肿瘤微环境(tumor microenvironment, TME)、微卫星不稳定/错配基因修复(microsatellite instability/mismatch repair, MSI/MMR)、肠道微生物群等。本文就不同指标在NSCLC免疫治疗的疗效预测价值展开探讨。
Abstract: In recent years, immune checkpoint inhibitors have made great progress in the treatment of non-small cell lung cancer. Immunotherapy of NSCLC has become one of the standard treatment methods following surgery, chemotherapy and radiotherapy. However, only some NSCLC patients benefit from ICIs treatment. Therefore, it is urgent to explore biomarkers that can predict the effi-cacy of ICIs and provide a basis for screening the population with clinical advantage. Programmed cell death ligand 1 (PD-L1) is the first explored indicator in immunotherapy, showing a certain pre-dictive role for the efficacy of immunotherapy, but with certain limitations. Other biomarkers have also been shown to be predictive, such as tumor mutation burden (TMB), tumor microenvironment (TME), microsatellite instability/mismatch repair (MSI/MMR), intestinal microflora, etc. In this study, we explored efficacy prediction value of different indicators in NSCLC immunotherapy.
文章引用：张科宇, 李索妮, 郑琪, 孙尚莹, 高芝兰, 赵征. 非小细胞肺癌免疫治疗疗效预测标志物研究进展[J]. 临床医学进展, 2023, 13(1): 264-271. https://doi.org/10.12677/ACM.2023.131041

参考文献

[1] Sung, H., Ferlay, J., Siegel, R.L., 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. [Google Scholar] [CrossRef] [PubMed]
[2] Mirhadi, S., Tam, S., Li, Q., et al. (2022) Integrative Analysis of Non-Small Cell Lung Cancer Patient-Derived Xenografts Identifies Distinct Proteotypes Associated with Patient Out-comes. Nature Communications, 13, 1811-1827. [Google Scholar] [CrossRef] [PubMed]
[3] Bie, F., Tian, H., Sun, N., et al. (2022) Research Progress of Anti-PD-1/PD-L1 Immunotherapy Related Mechanisms and Predictive Biomarkers in NSCLC. Frontiers in Oncology, 12, 769124-132. [Google Scholar] [CrossRef] [PubMed]
[4] Hui, E. (2019) Immune checkpoint inhibitors. Journal of Cell Biol-ogy, 218, 740-741. [Google Scholar] [CrossRef] [PubMed]
[5] Jiang, Y., Chen, M., Nie, H., et al. (2019) PD-1 and PD-L1 in Cancer Immunotherapy: Clinical Implications and Future Considerations. Human Vaccines & Immunotherapeutics, 15, 1111-1122. [Google Scholar] [CrossRef] [PubMed]
[6] Yi, M., Zheng, X., Niu, M., et al. (2022) Combination Strategies with PD-1/PD-L1 Blockade: Current Advances and Future Directions. Molecular Cancer, 21, 28-55. [Google Scholar] [CrossRef] [PubMed]
[7] Reck, M., Rodríguez-Abreu, D., Robinson, A.G., et al. (2021) Five-Year Outcomes with Pembrolizumab versus Chemotherapy for Metastatic Non-Small-Cell Lung Cancer with PD-L1 Tumor Proportion Score ≥ 50. Journal of Clinical Oncology, 39, 2339-2349. [Google Scholar] [CrossRef] 
[8] Mok, T., Wu, Y.L., Kudaba, I., et al. (2019) Pembrolizumab versus Chemotherapy for Previously Untreated, PD-L1- Expressing, Locally Advanced or Metastatic Non-Small-Cell Lung Cancer (KEYNOTE-042): A Randomised, Open- Label, Controlled, Phase 3 Trial. The Lancet, 393, 1819-1830. [Google Scholar] [CrossRef] 
[9] Gandhi, L., Rodríguez-Abreu, D., Gadgeel, S., et al. (2018) Pembrolizumab plus Chemotherapy in Metastatic Non- Small-Cell Lung Cancer. The New England Journal of Medicine, 378, 2078-2092. [Google Scholar] [CrossRef] 
[10] Socinski, M.A., Jotte, R.M., Cappuzzo, F., et al. (2018) Atezoli-zumab for First-Line Treatment of Metastatic Nonsquamous NSCLC. The New England Journal of Medicine, 378, 2288-2301. [Google Scholar] [CrossRef] 
[11] Paz-Ares, L., Luft, A., Vicente, D., et al. (2018) Pem-brolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer. The New England Journal of Medicine, 379, 2040-2051. [Google Scholar] [CrossRef] 
[12] Cascone, T., William, W.J., Weissferdt, A., et al. (2021) Neoadjuvant Nivolumab or Nivolumab plus Ipilimumab in Operable Non-Small Cell Lung Cancer: The Phase 2 Ran-domized NEOSTAR Trial. Nature Medicine, 27, 504-514. [Google Scholar] [CrossRef] [PubMed]
[13] Shu, C.A., Gainor, J.F., Awad, M.M., et al. (2020) Neoadjuvant Atezolizumab and Chemotherapy in Patients with Resectable Non-Small-Cell Lung Cancer: An Open-Label, Multicentre, Single-Arm, Phase 2 Trial. The Lancet Oncology, 21, 786-795. [Google Scholar] [CrossRef] 
[14] Kumar, U.S., Natarajan, A., Massoud, T.F., et al. (2022) FN3 Linked Nanobubbles as a Targeted Contrast Agent for US Imaging of Cancer-Associated Human PD-L1. Journal of Controlled Release, 346, 317-327. [Google Scholar] [CrossRef] [PubMed]
[15] Mei, J., Xu, J., Yang, X., et al. (2021) A Comparability Study of Natural and Deglycosylated PD-L1 Levels in Lung Cancer: Evidence from Immunohistochemical Analysis. Molecular Cancer, 20, 11-18. [Google Scholar] [CrossRef] [PubMed]
[16] Hellmann, M.D., Ciuleanu, T.E., Pluzanski, A., et al. (2018) Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden. The New England Journal of Medi-cine, 378, 2093-2104. [Google Scholar] [CrossRef] 
[17] Carbone, D.P., Reck, M., Paz-Ares, L., et al. (2017) First-Line Nivolumab in Stage IV or Recurrent Non-Small-Cell Lung Cancer. The New England Journal of Medicine, 376, 2415-2426. [Google Scholar] [CrossRef] 
[18] Kim, E.S., Velcheti, V., Mekhail, T., et al. (2022) Blood-Based Tumor Mutational Burden as a Biomarker for Atezolizumab in Non-Small Cell Lung Cancer: The Phase 2 B-F1RST Trial. Nature Medicine, 28, 939-945. [Google Scholar] [CrossRef] [PubMed]
[19] Brambilla, E., Le Teuff, G., Marguet, S., et al. (2016) Prognostic Effect of Tumor Lymphocytic Infiltration in Resectable Non-Small-Cell Lung Cancer. Journal of Clinical Oncology, 34, 1223-1230. [Google Scholar] [CrossRef] 
[20] Francini, E., Ou, F.S., Lazzi, S., et al. (2021) The Prognostic Value of CD3+ Tumor-Infiltrating Lymphocytes for Stage II Colon Cancer According to Use of Adjuvant Chemotherapy: A Large Single-Institution Cohort Study. Translational Oncology, 14, Article ID: 100973. [Google Scholar] [CrossRef] [PubMed]
[21] Chen, B., Li, H., Liu, C., et al. (2020) Prognostic Value of the Common Tumour-Infiltrating Lymphocyte Subtypes for Patients with Non-Small Cell Lung Cancer: A Meta-Analysis. PLOS ONE, 15, e0242173. [Google Scholar] [CrossRef] [PubMed]
[22] Fumet, J.D., Richard, C., Ledys, F., et al. (2018) Prognostic and Predictive Role of CD8 and PD-L1 Determination in Lung Tumor Tissue of Patients under Anti-PD-1 Therapy. British Journal of Cancer, 119, 950-960. [Google Scholar] [CrossRef] [PubMed]
[23] Mazzaschi, G., Madeddu, D., Falco, A., et al. (2018) Low PD-1 Expression in Cytotoxic CD8+ Tumor-Infiltrating Lymphocytes Confers an Immune-Privileged Tissue Microenvironment in NSCLC with a Prognostic and Predictive Value. Clinical Cancer Research, 24, 407-419. [Google Scholar] [CrossRef] 
[24] Yeong, J., Suteja, L., Simoni, Y., et al. (2021) Intratumoral CD39+CD8+ T Cells Predict Response to Programmed Cell Death Protein-1 or Programmed Death Ligand-1 Blockade in Patients with NSCLC. Journal of Thoracic Oncology, 16, 1349-1358. [Google Scholar] [CrossRef] [PubMed]
[25] Sanmamed, M.F., Nie, X., Desai, S.S., et al. (2021) A Burned-Out CD8+ T-Cell Subset Expands in the Tumor Microenvironment and Curbs Cancer Immunotherapy. Cancer Discovery, 11, 1700-1715. [Google Scholar] [CrossRef] 
[26] Teng, M.W., Ngiow, S.F., Ribas, A., et al. (2015) Classify-ing Cancers Based on T-Cell Infiltration and PD-L1. Cancer Research, 75, 2139-2145. [Google Scholar] [CrossRef] 
[27] Kudo, M. (2020) A New Era in Systemic Therapy for Hepatocellular Carcinoma: Atezolizumab plus Bevacizumab Combination Therapy. Liver Cancer, 9, 119-137. [Google Scholar] [CrossRef] [PubMed]
[28] Manabe, K., Yamasaki, O., Nakagawa, Y., et al. (2021) Multifunctionality of CD8+ T Cells and PD-L1 Expression as a Biomarker of Anti-PD-1 Antibody Efficacy in Advanced Melanoma. The Journal of Dermatology, 48, 1186-1192. [Google Scholar] [CrossRef] [PubMed]
[29] Zhang, L., Chen, Y., Wang, H., et al. (2021) Massive PD-L1 and CD8 Double Positive TILs Characterize an Immunosuppressive Microenvironment with High Mutational Burden in Lung Cancer. The Journal for ImmunoTherapy of Cancer, 9, e002356. [Google Scholar] [CrossRef] [PubMed]
[30] Xiang, X., Wang, J., Lu, D., et al. (2021) Targeting Tu-mor-Associated Macrophages to Synergize Tumor Immunotherapy. Signal Transduction and Targeted Therapy, 6, 75-86. [Google Scholar] [CrossRef] [PubMed]
[31] 乔艳艳, 傅恩清. 肿瘤相关巨噬细胞在肺癌中的研究进展[J]. 中国肺癌杂志, 2022, 25(1): 34-39.
[32] Romano, E., Kusio-Kobialka, M., Foukas, P.G., et al. (2015) Ipili-mumab-Dependent Cell-Mediated Cytotoxicity of Regulatory T Cells ex Vivo by Nonclassical Monocytes in Melanoma Patients. Proceedings of the National Academy of Sciences of the United States of America, 112, 6140-6145. [Google Scholar] [CrossRef] [PubMed]
[33] Liu, Y., Zugazagoitia, J., Ahmed, F.S., et al. (2020) Immune Cell PD-L1 Colocalizes with Macrophages and Is Associated with Outcome in PD-1 Pathway Blockade Therapy. Clinical Cancer Research, 26, 970-977. [Google Scholar] [CrossRef] 
[34] Ben-Shmuel, A., Biber, G. and Barda-Saad, M. (2020) Un-leashing Natural Killer Cells in the Tumor Microenvironment— The Next Generation of Immunotherapy? Frontiers in Immunology, 11, 275-297. [Google Scholar] [CrossRef] [PubMed]
[35] Riaz, N., Havel, J.J., Makarov, V., et al. (2017) Tumor and Mi-croenvironment Evolution during Immunotherapy with Nivolumab. Cell, 171, 934-949. [Google Scholar] [CrossRef] [PubMed]
[36] Le, D.T., Uram, J.N., Wang, H., et al. (2015) PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. The New England Journal of Medicine, 372, 2509-2520. [Google Scholar] [CrossRef] 
[37] Fanale, D., Corsini, L.R., Scalia, R., et al. (2022) Can the Tu-mor-Agnostic Evaluation of MSI/MMR Status Be the Common Denominator for the Immunotherapy Treatment of Pa-tients with Several Solid Tumors? Critical Reviews in Oncology/Hematology, 170, Article ID: 103597. [Google Scholar] [CrossRef] [PubMed]
[38] Lenz, H.J., Van Cutsem, E., Luisa, L.M., et al. (2022) First-Line Nivolumab Plus Low-Dose Ipilimumab for Microsatellite Instability-High/Mismatch Repair-Deficient Meta-static Colorectal Cancer: The Phase II CheckMate 142 Study. Journal of Clinical Oncology, 40, 161-170. [Google Scholar] [CrossRef] 
[39] Diaz, L.J., Shiu, K.K., Kim, T.W., et al. (2022) Pembrolizumab versus Chemotherapy for Microsatellite Instability-High or Mismatch Repair-Deficient Metastatic Colorectal Cancer (KEYNOTE-177): Final Analysis of a Randomised, Open-Label, Phase 3 Study. The Lancet Oncology, 23, 659-670. [Google Scholar] [CrossRef] 
[40] 丁培荣. 微卫星高度不稳定结直肠癌的免疫治疗[J]. 中华胃肠外科杂志, 2022, 25(3): 199-204.
[41] Sepich-Poore G D, Zitvogel L, Straussman R, et al. (2021) The Micro-biome and Human Cancer. Science, 371, 4552-4586. [Google Scholar] [CrossRef] [PubMed]
[42] Hopkins, A.M., Badaoui, S., Kichenadasse, G., et al. (2022) Efficacy of Atezolizumab in Patients with Advanced NSCLC Receiving Concomitant Antibiotic or Proton Pump Inhibitor Treat-ment: Pooled Analysis of Five Randomized Control Trials. Journal of Thoracic Oncology, 17, 758-767. [Google Scholar] [CrossRef] [PubMed]
[43] Derosa, L., Routy, B., Thomas, A.M., et al. (2022) Intestinal Ak-kermansia muciniphila Predicts Clinical Response to PD-1 Blockade in Patients with Advanced Non-Small-Cell Lung Cancer. Nature Medicine, 28, 315-324. [Google Scholar] [CrossRef] [PubMed]
[44] Lee, S.H., Cho, S.Y., Yoon, Y., et al. (2021) Bifidobacterium bifidum Strains Synergize with Immune Checkpoint Inhibitors to Reduce Tumour Burden in Mice. Nature Microbiology, 6, 277-288. [Google Scholar] [CrossRef] [PubMed]
[45] Hakozaki, T., Richard, C., Elkrief, A., et al. (2020) The Gut Mi-crobiome Associates with Immune Checkpoint Inhibition Outcomes in Patients with Advanced Non-Small Cell Lung Cancer. Cancer Immunology Research, 8, 1243-1250. [Google Scholar] [CrossRef] 

为你推荐