外周血生物标志物在非小细胞肺癌免疫治疗疗效预测研究进展
Progress of Peripheral Blood Biomarkers in Predicting the Efficacy of Immunotherapy for Non-Small Cell Lung Cancer
摘要: 近年来,以免疫检查点抑制剂(ICIs)为代表的免疫治疗在非小细胞肺癌(NSCLC)综合治疗中已经取得重大突破,彻底更改了不同期别NSCLC的整体治疗策略。虽然肿瘤组织相关标记物如:细胞程序性死亡–配体1 (PD-L1)、肿瘤突变负荷(TMB)等能在一定程度上很好的预测应答反应;但受制于肿瘤标本获取、检测技术、经济负担等因素,限制其在临床大规模应用,如何早期、高效、无创的识别免疫治疗的潜在获益人群是当务之急。外周血成为理想的样本来源,也显示了作为免疫治疗效果预测因子的潜力。本文旨在综述外周血生物标志物在NSCLC免疫治疗疗效预测研究进展,为后续临床治疗提供参考依据。
Abstract: In recent years, immunotherapy represented by immune checkpoint inhibitors (ICIs) has made significant breakthroughs in the comprehensive treatment of non-small cell lung cancer (NSCLC), completely changing the overall treatment strategy of NSCLC of different stages. Although tumor tissue-associated markers such as programmed cell death-ligand 1 (PD-L1) and tumor mutational load (TMB) can predict response well to a certain extent; however, factors such as tumor specimen acquisition, detection technology, and economic burden limit their large-scale clinical application, and it is imperative to identify the potential beneficiary populations of immunotherapy in an early, efficient, and non-invasive manner. Peripheral blood has become an ideal sample source and has also shown potential as a predictor of immunotherapy efficacy. The aim of this article is to review the progress of peripheral blood biomarkers in NSCLC immunotherapy efficacy prediction research, and provide a reference basis for subsequent clinical treatment.
文章引用:孙维蔚, 贾敬好. 外周血生物标志物在非小细胞肺癌免疫治疗疗效预测研究进展[J]. 临床医学进展, 2024, 14(2): 4445-4452. https://doi.org/10.12677/ACM.2024.142617

参考文献

[1] Sung, H., 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] Xia, L., et al. (2019) PD-1/PD-L1 Blockade Therapy in Advanced Non-Small-Cell Lung Cancer: Current Status and Future Directions. The Oncologist, 24, S31-S41. [Google Scholar] [CrossRef
[3] Miao, K., et al. (2022) Real-World Data of Different Immune Checkpoint Inhibitors for Non-Small Cell Lung Cancer in China. Frontiers in Oncology, 12, Article 859938. [Google Scholar] [CrossRef] [PubMed]
[4] Negrao, M.V., et al. (2021) Oncogene-Specific Differences in Tu-mor Mutational Burden, PD-L1 Expression, and Outcomes from Immunotherapy in Non-Small Cell Lung Cancer. Jour-nal for Immunotherapy of Cancer, 9, e002891. [Google Scholar] [CrossRef] [PubMed]
[5] Aguilar, E.J., et al. (2019) Outcomes to First-Line Pembrolizumab in Patients with Non-Small-Cell Lung Cancer and Very High PD-L1 Expression. Annals of Oncology, 30, 1653-1659. [Google Scholar] [CrossRef] [PubMed]
[6] Doroshow, D.B., et al. (2021) PD-L1 as a Biomarker of Response to Immune-Checkpoint Inhibitors. Nature Reviews. Clinical Oncology, 18, 345-362. [Google Scholar] [CrossRef] [PubMed]
[7] Bravaccini, S., et al. (2021) TMB in NSCLC: A Broken Dream? International Journal of Molecular Sciences, 22, Article 6536. [Google Scholar] [CrossRef] [PubMed]
[8] Li, S., et al. (2020) Emerging Blood-Based Biomarkers for Predicting Response to Checkpoint Immunotherapy in Non-Small-Cell Lung Cancer. Frontiers in Immunology, 11, Article 603157. [Google Scholar] [CrossRef] [PubMed]
[9] de Visser, K.E. and Joyce, J.A. (2023) The Evolving Tumor Mi-croenvironment: From Cancer Initiation to Metastatic Outgrowth. Cancer Cell, 41, 374-403. [Google Scholar] [CrossRef] [PubMed]
[10] Sharma, P., et al. (2017) Primary, Adaptive, and Acquired Re-sistance to Cancer Immunotherapy. Cell, 168, 707-723. [Google Scholar] [CrossRef] [PubMed]
[11] Daassi, D., et al. (2020) The Importance of Exosomal PDL1 in Tu-mour Immune Evasion. Nature Reviews. Immunology, 20, 209-215. [Google Scholar] [CrossRef] [PubMed]
[12] Niu, M., et al. (2022) Biological Characteristics and Clinical Sig-nificance of Soluble PD-1/PD-L1 and Exosomal PD- L1 in Cancer. Frontiers in Immunology, 13, Article 827921. [Google Scholar] [CrossRef] [PubMed]
[13] Murakami, S., et al. (2020) Association Between Serum Level Soluble Programmed Cell Death Ligand 1 and Prognosis in Patients with Non-Small Cell Lung Cancer Treated with An-ti-PD-1 Antibody. Thoracic Cancer, 11, 3585-3595. [Google Scholar] [CrossRef] [PubMed]
[14] Scirocchi, F., et al. (2022) Soluble PD-L1 as a Prognostic Factor for Immunotherapy Treatment in Solid Tumors: Systematic Review and Meta-Analysis. International Journal of Molecular Sciences, 23, Article 14496. [Google Scholar] [CrossRef] [PubMed]
[15] Morrissey, S.M. and Yan, J. (2020) Exosomal PD-L1: Roles in Tu-mor Progression and Immunotherapy. Trends in Cancer, 6, 550-558. [Google Scholar] [CrossRef] [PubMed]
[16] Kim, D.H., et al. (2019) Exosomal PD-L1 Promotes Tumor Growth through Immune Escape in Non-Small Cell Lung Cancer. Experimental & Molecular Medicine, 51, 1-13. [Google Scholar] [CrossRef] [PubMed]
[17] Li, C., et al. (2019) Clinical Significance of PD-L1 Expression in Serum-Derived Exosomes in NSCLC Patients. Journal of Translational Medicine, 17, Article No. 355. [Google Scholar] [CrossRef] [PubMed]
[18] Yang, Q., et al. (2021) Novel Biomarkers of Dynamic Blood PD-L1 Expression for Immune Checkpoint Inhibitors in Advanced Non-Small-Cell Lung Cancer Patients. Frontiers in Immunology, 12, Article 665133. [Google Scholar] [CrossRef] [PubMed]
[19] Mazel, M., et al. (2015) Frequent Expression of PD-L1 on Cir-culating Breast Cancer Cells. Molecular Oncology, 9, 1773-1782. [Google Scholar] [CrossRef] [PubMed]
[20] Guibert, N., et al. (2018) PD-L1 Expression in Circulating Tu-mor Cells of Advanced Non-Small Cell Lung Cancer Patients Treated with Nivolumab. Lung Cancer (Amsterdam, Netherlands), 120, 108-112. [Google Scholar] [CrossRef] [PubMed]
[21] Nicolazzo, C., et al. (2016) Monitoring PD-L1 Positive Circu-lating Tumor Cells in Non-Small Cell Lung Cancer Patients Treated with the PD-1 Inhibitor Nivolumab. Scientific Re-ports, 6, Article No. 31726. [Google Scholar] [CrossRef] [PubMed]
[22] Indini, A., et al. (2021) Circulating Biomarkers of Response and Toxicity of Immunotherapy in Advanced Non-Small Cell Lung Cancer (NSCLC): A Comprehensive Review. Cancers, 13, Article 1794. [Google Scholar] [CrossRef] [PubMed]
[23] Strati, A., et al. (2023) Clinical Significance of PD-L1 Status in Cir-culating Tumor Cells for Cancer Management During Immunotherapy. Biomedicines, 11, Article 1768. [Google Scholar] [CrossRef] [PubMed]
[24] Hinterleitner, C., et al. (2021) Platelet PD-L1 Reflects Collec-tive Intratumoral PD-L1 Expression and Predicts Immunotherapy Response in Non-Small Cell Lung Cancer. Nature Communications, 12, Article No. 7005. [Google Scholar] [CrossRef] [PubMed]
[25] Gandara, D.R., et al. (2018) Blood-Based Tumor Mutational Burden as a Predictor of Clinical Benefit in Non-Small- Cell Lung Cancer Patients Treated with Atezolizumab. Nature Medicine, 24, 1441-1448. [Google Scholar] [CrossRef] [PubMed]
[26] Si, H., et al. (2021) A Blood-Based Assay for Assessment of Tumor Mutational Burden in First-Line Metastatic NSCLC Treatment: Results from the MYSTIC Study. Clinical Cancer Research, 27, 1631-1640. [Google Scholar] [CrossRef
[27] Kim, E.S., 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]
[28] Stetson, D., et al. (2019) Orthogonal Comparison of Four Plasma NGS Tests with Tumor Suggests Technical Factors Are a Major Source of Assay Discordance. JCO Precision Oncology, 3, 1-9. [Google Scholar] [CrossRef
[29] Liu, Z., et al. (2019) Presence of Allele Frequency Heterogeneity Defined by CtDNA Profiling Predicts Unfavorable Overall Survival of NSCLC. Translational Lung Cancer Research, 8, 1045-1050. [Google Scholar] [CrossRef] [PubMed]
[30] Nie, W., et al. (2022) CtDNA-Adjusted BTMB as a Predictive Bi-omarker for Patients with NSCLC Treated with PD- (L)1 Inhibitors. BMC Medicine, 20, Article No. 170. [Google Scholar] [CrossRef] [PubMed]
[31] Hedrick, C.C. and Malanchi, I. (2022) Neutrophils in Cancer: Heterogeneous and Multifaceted. Nature Reviews. Immunology, 22, 173-187. [Google Scholar] [CrossRef] [PubMed]
[32] Gungabeesoon, J., et al. (2023) A Neutrophil Response Linked to Tumor Control in Immunotherapy. Cell, 186, 1448- 1464.e20. [Google Scholar] [CrossRef] [PubMed]
[33] Tanizaki, J., et al. (2018) Peripheral Blood Biomarkers Associated with Clinical Outcome in Non-Small Cell Lung Cancer Patients Treated with Nivolumab. Journal of Thoracic Oncology, 13, 97-105. [Google Scholar] [CrossRef] [PubMed]
[34] Saini, R. and Singh, S. (2019) Inducible Nitric Oxide Synthase: An Asset to Neutrophils. Journal of Leukocyte Biology, 105, 49-61. [Google Scholar] [CrossRef
[35] Hirschhorn, D., et al. (2023) T Cell Immunotherapies Engage Neutrophils to Eliminate Tumor Antigen Escape Variants. Cell, 186, 1432-1447.e17. [Google Scholar] [CrossRef] [PubMed]
[36] Cao, D., et al. (2018) A Reliable and Feasible Way to Predict the Benefits of Nivolumab in Patients with Non-Small Cell Lung Cancer: A Pooled Analysis of 14 Retrospective Studies. Oncoimmunology, 7, e1507262. [Google Scholar] [CrossRef
[37] Chen, Y., et al. (2021) Association of Dynamic Changes in Peripheral Blood Indexes with Response to PD-1 Inhibitor-Based Combination Therapy and Survival Among Patients with Advanced Non-Small Cell Lung Cancer. Frontiers in Immunology, 12, Article 672271. [Google Scholar] [CrossRef] [PubMed]
[38] Mezquita, L., et al. (2021) Predicting Immunotherapy Outcomes under Therapy in Patients with Advanced NSCLC Using DNLR and Its Early Dynamics. European Journal of Cancer (Oxford, England: 1990), 151, 211-220. [Google Scholar] [CrossRef] [PubMed]
[39] Alessi, J.V., et al. (2021) Low Peripheral Blood Derived Neutro-phil-to-Lymphocyte Ratio (DNLR) Is Associated with Increased Tumor T-Cell Infiltration and Favorable Outcomes to First-Line Pembrolizumab in Non-Small Cell Lung Cancer. Journal for Immunotherapy of Cancer, 9, e003536. [Google Scholar] [CrossRef] [PubMed]
[40] Li, Y., et al. (2020) Pretreatment Neutrophil-to-Lymphocyte Ratio (NLR) May Predict the Outcomes of Advanced Non-Small-Cell Lung Cancer (NSCLC) Patients Treated with Immune Checkpoint Inhibitors (ICIs). Frontiers in Oncology, 10, Article 654. [Google Scholar] [CrossRef] [PubMed]
[41] Holtzman, L., et al. (2022) dNLR-Based Score Predicting Overall Survival Benefit for the Addition of Platinum-Based Chemotherapy to Pembrolizumab in Advanced NSCLC with PD-L1 Tumor Proportion Score ≥ 50. Clinical Lung Cancer, 23, 122-134. [Google Scholar] [CrossRef] [PubMed]
[42] Diem, S., et al. (2017) Neutrophil-to-Lymphocyte Ratio (NLR) and Platelet-to-Lymphocyte Ratio (PLR) as Prognostic Markers in Patients with Non-Small Cell Lung Cancer (NSCLC) Treated with Nivolumab. Lung Cancer (Amsterdam, Netherlands), 111, 176-181. [Google Scholar] [CrossRef] [PubMed]
[43] Zheng, L., et al. (2023) Decreased Monocyte-to-Lymphocyte Ratio Was Associated with Satisfied Outcomes of First-Line PD-1 Inhibitors Plus Chemotherapy in Stage IIIB-IV Non-Small Cell Lung Cancer. Frontiers in Immunology, 14, Article 1094378. [Google Scholar] [CrossRef] [PubMed]
[44] Ma, C., et al. (2022) Platelets Control Liver Tumor Growth through P2Y12-Dependent CD40L Release in NAFLD. Cancer Cell, 40, 986-998.e5. [Google Scholar] [CrossRef] [PubMed]
[45] Pankowska, K.A., et al. (2023) Crosstalk of Immune Cells and Platelets in an Ovarian Cancer Microenvironment and Their Prognostic Significance. International Journal of Molecular Sciences, 24, Article 9279. [Google Scholar] [CrossRef] [PubMed]
[46] Zhang, G., et al. (2022) Clinical Predictive Value of Naïve and Memory T Cells in Advanced NSCLC. Frontiers in Immunology, 13, Article 996348. [Google Scholar] [CrossRef] [PubMed]
[47] Wang, Y.-Y., et al. (2020) Circulating Activated Lymphocyte Subsets as Potential Blood Biomarkers of Cancer Progression. Cancer Medicine, 9, 5086-5094. [Google Scholar] [CrossRef] [PubMed]
[48] Huang, A.C., et al. (2017) T-Cell Invigoration to Tumour Burden Ratio Associated with Anti-PD-1 Response. Nature, 545, 60-65. [Google Scholar] [CrossRef] [PubMed]
[49] Nabet, B.Y., et al. (2020) Noninvasive Early Identification of Therapeutic Benefit from Immune Checkpoint Inhibition. Cell, 183, 363-376.e13. [Google Scholar] [CrossRef] [PubMed]
[50] Kim, K.H., et al. (2019) The First-Week Proliferative Response of Peripheral Blood PD-1+CD8+ T Cells Predicts the Response to Anti-PD-1 Therapy in Solid Tumors. Clini-cal Cancer Research, 25, 2144-2154. [Google Scholar] [CrossRef
[51] Han, J., et al. (2020) TCR Repertoire Diversity of Peripheral PD-1+CD8+ T Cells Predicts Clinical Outcomes after Immunotherapy in Patients with Non-Small Cell Lung Cancer. Cancer Immunology Research, 8, 146-154. [Google Scholar] [CrossRef
[52] Borst, J., et al. (2018) CD4+ T Cell Help in Cancer Immu-nology and Immunotherapy. Nature Reviews. Immunology, 18, 635-647. [Google Scholar] [CrossRef] [PubMed]
[53] Kruse, B., et al. (2023) CD4+ T Cell-Induced Inflammatory Cell Death Controls Immune-Evasive Tumours. Nature, 618, 1033-1040. [Google Scholar] [CrossRef] [PubMed]
[54] Miao, K., et al. (2022) Peripheral Blood Lymphocyte Subsets Predict the Efficacy of Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer. Frontiers in Immunology, 13, Ar-ticle 912180. [Google Scholar] [CrossRef] [PubMed]
[55] 戴斌, 黄翠萍, 曹喆, 等. PD-1抑制剂对晚期非小细胞肺癌患者T淋巴细胞亚群、NK细胞及抑制性免疫检查点的影响[J]. 中国老年学杂志, 2021, 41(7): 1393-1396.
[56] Sui, H., et al. (2022) Immunotherapy of Targeting MDSCs in Tumor Microenvironment. Frontiers in Immunology, 13, Arti-cle 990463. [Google Scholar] [CrossRef] [PubMed]
[57] Youn, J.-I., et al. (2020) Peripheral Natural Killer Cells and Myeloid-Derived Suppressor Cells Correlate with Anti-PD-1 Responses in Non-Small Cell Lung Cancer. Sci-entific Reports, 10, Article No. 9050. [Google Scholar] [CrossRef] [PubMed]
[58] Kim, H.R., et al. (2019) The Ratio of Peripheral Regulatory T Cells to Lox-1+ Polymorphonuclear Myeloid-Derived Suppressor Cells Predicts the Early Response to Anti-PD-1 Ther-apy in Patients with Non-Small Cell Lung Cancer. American Journal of Respiratory and Critical Care Medicine, 199, 243-246. [Google Scholar] [CrossRef
[59] Sanmamed, M.F., et al. (2017) Changes in Serum Interleukin-8 (IL-8) Levels Reflect and Predict Response to Anti-PD-1 Treatment in Melanoma and Non-Small-Cell Lung Cancer Pa-tients. Annals of Oncology, 28, 1988-1995. [Google Scholar] [CrossRef] [PubMed]
[60] Keegan, A., et al. (2020) Plasma IL-6 Changes Correlate to PD-1 In-hibitor Responses in NSCLC. Journal for Immunotherapy of Cancer, 8, e000678. [Google Scholar] [CrossRef] [PubMed]
[61] Riedl, J.M., et al. (2020) C-Reactive Protein (CRP) Levels in Im-mune Checkpoint Inhibitor Response and Progression in Advanced Non-Small Cell Lung Cancer: A Bi-Center Study. Cancers, 12, Article 2319. [Google Scholar] [CrossRef] [PubMed]
[62] Klümper, N., et al. (2022) C Reactive Protein Flare Predicts Re-sponse to Checkpoint Inhibitor Treatment in Non-Small Cell Lung Cancer. Journal for Immunotherapy of Cancer, 10, e004024. [Google Scholar] [CrossRef] [PubMed]
[63] Mezquita, L., et al. (2018) Association of the Lung Im-mune Prognostic Index with Immune Checkpoint Inhibitor Outcomes in Patients with Advanced Non-Small Cell Lung Cancer. JAMA Oncology, 4, 351-357. [Google Scholar] [CrossRef] [PubMed]
[64] Madeddu, C., et al. (2023) Effect of Cancer-Related Cachexia and Associated Changes in Nutritional Status, Inflammatory Status, and Muscle Mass on Immunotherapy Efficacy and Survival in Patients with Advanced Non-Small Cell Lung Cancer. Cancers, 15, Article 1076. [Google Scholar] [CrossRef] [PubMed]