肿瘤免疫治疗疗效预测标志物的研究进展

doi:10.3760/cma.j.cn371439-20200722-00044

摘要/Abstract

摘要：

免疫检查点抑制剂成为近年来肿瘤治疗的热点,越来越多的肿瘤患者从免疫治疗中获益。由于免疫治疗费用较高,未检测人群免疫治疗获益率仅为20%。因此,精准地选择预测性生物标志物对于肿瘤患者个体化免疫治疗至关重要。反映肿瘤免疫微环境和肿瘤细胞内在特征的生物标志物,如程序性死亡蛋白1(PD-1)及其配体PD-L1、肿瘤突变负荷、微卫星不稳定性等,均已被证实与抗PD-1/PD-L1治疗效果相关。同时,基于组织和血清的标志物层出不穷,如何真正实现精确的肿瘤免疫治疗仍有待进一步临床研究。

关键词: 肿瘤, 免疫疗法, 生物标记,肿瘤, 免疫检查点抑制剂

Abstract:

Immonocheckpoint inhabitors have become the focus of tumor therapy in recent years, and more and more tumor patients benefit from immunotherapy. Due to the high cost of immunotherapy, the benefit rate of immunotherapy for untested population is only 20%. Therefore, accurate selection of predictive biomarkers is crucial for individualized immunotherapy of tumor patients. Biomarkers reflecting tumor immune microenvironment and tumor cell intrinsic features, such as programmed death-1 (PD-1) and its ligand PD-L1, tumor mutational burden and microsatellite instability, have been proved to associate with treatment effect of anti-PD-1/anti-PD-L1 therapy. At the same time, markers based on tissue and serum emerge in endlessly. How to truly achieve accurate immunotherapy for tumor needs further clinical research.

Key words: Neoplasms, Immunotherapy, Biomarkers,tumor, Immunocheckpoint inhibitors

李谡瑶, 黄俊星. 肿瘤免疫治疗疗效预测标志物的研究进展[J]. 国际肿瘤学杂志, 2021, 48(4): 220-224.

Li Suyao, Huang Junxing. Research progress of biomarkers for predicting the efficacy of immunotherapy for tumor[J]. Journal of International Oncology, 2021, 48(4): 220-224.

参考文献 44

[1]	Yu S, Li A, Liu Q, et al. Chimeric antigen receptor T cells: a novel therapy for solid tumors[J]. J Hematol Oncol, 2017, 10(1):78. DOI: 10.1186/s13045-017-0444-9. doi: 10.1186/s13045-017-0444-9
[2]	Yu S, Liu Q, Han X, et al. Development and clinical application of anti-HER2 monoclonal and bispecific antibodies for cancer treatment[J]. Exp Hematol Oncol, 2017, 6:31. DOI: 10.1186/s40164-017-0091-4. doi: 10.1186/s40164-017-0091-4
[3]	Peng M, Mo Y, Wang Y, et al. Neoantigen vaccine: an emerging tumorimmunotherapy[J]. Mol Cancer, 2019, 18(1):128. DOI: 10.1186/s12943-019-1055-6. doi: 10.1186/s12943-019-1055-6
[4]	Killock D. Skin cancer: T-VEC oncolytic viral therapy shows promise in melanoma[J]. Nat Rev Clin Oncol, 2015, 12(8):438. DOI: 10.1038/nrclinonc.2015.106. doi: 10.1038/nrclinonc.2015.106 pmid: 26077044
[5]	Li B, Chan HL, Chen P. Immune checkpoint inhibitors: basics and challenges[J]. Curr Med Chem, 2019, 26(17):3009-3025. DOI: 10.2174/0929867324666170804143706. doi: 10.2174/0929867324666170804143706
[6]	Balar AV, Castellano D, O'Donnell PH, et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study[J]. Lancet Oncol, 2017, 18(11):1483-1492. DOI: 10.1016/S1470-2045(17)30616-2. doi: 10.1016/S1470-2045(17)30616-2
[7]	Valsecchi ME. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma[J]. N Engl J Med, 2015, 373(13): 1270. DOI: 10.1056/NEJMc1509660.
[8]	Hodi FS, Chiarion-Sileni V, Gonzalez R, et al. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, rando-mised, phase 3 trial[J]. Lancet Oncol, 2018, 19(11):1480-1492. DOI: 10.1016/S1470-2045(18)30700-9. doi: 10.1016/S1470-2045(18)30700-9
[9]	Rittmeyer A, Barlesi F, Waterkamp D, et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomized controlled trial[J]. Lancet, 2017, 389(10066):255-265. DOI: 10.1016/S0140-6736(16)32517-X. doi: S0140-6736(16)32517-X pmid: 27979383
[10]	Reck M, Rodríguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer[J]. N Engl J Med, 2016, 375(19):1823-1833. DOI: 10.1056/NEJMoa1606774. doi: 10.1056/NEJMoa1606774
[11]	Mansfield AS, Aubry MC, Moser JC, et al. Temporal and spatial discordance of programmed cell death-ligand 1 expression and lymphocyte tumor infiltration between paired primary lesions and brain metastases in lung cancer[J]. Ann Oncol, 2016, 27(10):1953-1958. DOI: 10.1093/annonc/mdw289. doi: 10.1093/annonc/mdw289
[12]	Zhou J, Gong Z, Jia Q, et al. Programmed death ligand 1 expression and CD8⁺ tumor-infiltrating lymphocyte density differences between paired primary and brain metastatic lesions in non-small cell lung cancer [J]. Biochem Biophys Res Commun, 2018, 498(4):751-757. DOI: 10.1016/j.bbrc.2018.03.053. doi: 10.1016/j.bbrc.2018.03.053
[13]	Tímár J, Ladányi A. A daganatok immunterápiájának prediktív markerei, a PD-L1-meghatározás gyakorlati kérdései [Predictive markers of immunotherapy of cancer, practical issues of PD-L1 testing][J]. Magy Onkol, 2017, 61(2):158-166.
[14]	Gupta D, Heinen CD. The mismatch repair-dependent DNA damage response: mechanisms and implications[J]. DNA Repair (Amst), 2019, 78:60-69. DOI: 10.1016/j.dnarep.2019.03.009. doi: 10.1016/j.dnarep.2019.03.009
[15]	Yuza K, Nagahashi M, Watanabe S, et al. Hypermutation and microsatellite instability in gastrointestinal cancers[J]. Oncotarget, 2017, 8(67):112103-112115. DOI: 10.18632/oncotarget.22783. doi: 10.18632/oncotarget.v8i67
[16]	Kim ST, Klempner SJ, Park SH, et al. Correlating programmed death ligand 1 (PD-L1) expression, mismatch repair deficiency, and outcomes across tumor types: implications for immunotherapy[J]. Oncotarget, 2017, 8(44):77415-77423. DOI: 10.18632/oncotarget.20492. doi: 10.18632/oncotarget.v8i44
[17]	Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade[J]. Science, 2017, 357(6349):409-413. DOI: 10.1126/science.aan6733. doi: 10.1126/science.aan6733
[18]	Jin Z, Yoon HH. The promise of PD-1 inhibitors in gastro-esopha-geal cancers: microsatellite instability vs. PD-L1[J]. J Gastrointest Oncol, 2016, 7(5):771-788. DOI: 10.21037/jgo.2016.08.06. doi: 10.21037/jgo
[19]	Chang L, Chang M, Chang HM, et al. Microsatellite instability: a predictive biomarker for cancer immunotherapy[J]. Appl Immunohistochem Mol Morphol, 2018, 26(2):e15-e21. DOI: 10.1097/PAI.0000000000000575.
[20]	Chen C, Zhang F, Zhou N, et al. Efficacy and safety of immune checkpoint inhibitors in advanced gastric or gastroesophageal junction cancer: a systematic review and meta-analysis[J]. Oncoimmunology, 2019, 8(5):e1581547. DOI: 10.1080/2162402X.2019.1581547. doi: 10.1080/2162402X.2019.1581547
[21]	Mills AM, Dill EA, Moskaluk CA, et al. The relationship between mismatch repair deficiency and PD-L1 expression in breast carcinoma[J]. Am J Surg Pathol, 2018, 42(2):183-191. DOI: 10.1097/PAS.0000000000000949. doi: 10.1097/PAS.0000000000000949
[22]	El Jabbour T, Ross JS, Sheehan CE, et al. PD-L1 protein expression in tumour cells and immune cells in mismatch repair protein-deficient and -proficient colorectal cancer: the foundation study using the SP142 antibody and whole section immunohistochemistry[J]. J Clin Pathol, 2018, 71(1):46-51. DOI: 10.1136/jclinpath-2017-204525. doi: 10.1136/jclinpath-2017-204525
[23]	Rooney MS, Shukla SA, Wu CJ, et al. Molecular and genetic pro-perties of tumors associated with local immune cytolytic activity[J]. Cell, 2015, 160(1- 2):48-61. DOI: 10.1016/j.cell.2014.12.033. doi: 10.1016/j.cell.2014.12.036
[24]	Ott PA, Bang YJ, Piha-Paul SA, et al. T-cell-inflamed gene-expression profile, programmed death ligand 1 expression, and tumor mutational burden predict efficacy in patients treated with pembrolizumab across 20 cancers: KEYNOTE-028[J]. J Clin Oncol, 2019, 37(4):318-327. DOI: 10.1200/JCO.2018.78.2276.
[25]	Chan TA, Yarchoan M, Jaffee E, et al. Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic[J]. Ann Oncol, 2019, 30(1):44-56. DOI: 10.1093/annonc/mdy495. doi: 10.1093/annonc/mdy495
[26]	Samstein RM, Lee CH, Shoushtari AN, et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types[J]. Nat Genet, 2019, 51(2):202-206. DOI: 10.1038/s41588-018-0312-8. doi: 10.1038/s41588-018-0312-8
[27]	Carbone DP, Reck M, Paz-Ares L, et al. First-line nivolumab in stage Ⅳ or recurrent non-small-cell lung cancer[J]. N Engl J Med, 2017, 376(25):2415-2426. DOI: 10.1056/NEJMoa1613493. doi: 10.1056/NEJMoa1613493
[28]	Krieg C, Nowicka M, Guglietta S, et al. High-dimensional single-cell analysis predicts response to anti-PD-1 immunotherapy[J]. Nat Med, 2018, 24(2):144-153. DOI: 10.1038/nm.4466.
[29]	Kamphorst AO, Pillai RN, Yang S, et al. Proliferation of PD-1⁺ CD8 T cells in peripheral blood after PD-1-targeted therapy in lung cancer patients [J]. Proc Natl Acad Sci U S A, 2017, 114(19):4993-4998. DOI: 10.1073/pnas.1705327114. doi: 10.1073/pnas.1705327114
[30]	Fujisawa Y, Yoshino K, Otsuka A, et al. Baseline neutrophil to lymphocyte ratio combined with serum LDH level associated with outcome of nivolumab immunotherapy in a Japanese advanced melanoma population[J]. Br J Dermatol, 2018, 179(1):213-215. DOI: 10.1111/bjd.16427. doi: 10.1111/bjd.16427
[31]	Soyano AE, Dholaria B, Marin-Acevedo JA, et al. Peripheral blood biomarkers correlate with outcomes in advanced non-small cell lung cancer patients treated with anti-PD-1 antibodies[J]. J Immunother Cancer, 2018, 6(1): 129. DOI: 10.1186/s40425-018-0447-2.
[32]	Tanizaki J, Haratani K, Hayashi H, et al. Peripheral blood biomarkers associated with clinical outcome in non-small cell lung cancer patients treated with nivolumab[J]. J Thorac Oncol, 2018, 13(1):97-105. DOI: 10.1016/j.jtho.2017.10.030. doi: S1556-0864(17)33008-3 pmid: 29170120
[33]	Mitsuhashi A, Okuma Y. Perspective on immune oncology with liquid biopsy, peripheral blood mononuclear cells, and microbiome with noninvasive biomarkers in cancer patients[J]. Clin Transl Oncol, 2018, 20(8):966-974. DOI: 10.1007/s12094-017-1827-7. doi: 10.1007/s12094-017-1827-7 pmid: 29313208
[34]	Caponnetto S, Iannantuono GM, Barchiesi G, et al. Prolactin as a potential early predictive factor in metastatic non-small cell lung cancer patients treated with nivolumab[J]. Oncology, 2017, 93(1):62-66. DOI: 10.1159/000464328. doi: 10.1159/000464328 pmid: 28407622
[35]	Yamazaki N, Kiyohara Y, Uhara H, et al. Cytokine biomarkers to predict antitumor responses to nivolumab suggested in a phase 2 study for advanced melanoma[J]. Cancer Sci, 2017, 108(5):1022-1031. DOI: 10.1111/cas.13226. doi: 10.1111/cas.13226
[36]	Ilié M, Szafer-Glusman E, Hofman V, et al. Detection of PD-L1 in circulating tumor cells and white blood cells from patients with advanced non-small-cell lung cancer[J]. Ann Oncol, 2018, 29(1):193-199. DOI: 10.1093/annonc/mdx636. doi: 10.1093/annonc/mdx636
[37]	Cabel L, Proudhon C, Romano E, et al. Clinical potential of circulating tumour DNA in patients receiving anticancer immunotherapy[J]. Nat Rev Clin Oncol, 2018, 15(10):639-650. DOI: 10.1038/s41571-018-0074-3. doi: 10.1038/s41571-018-0074-3 pmid: 30050094
[38]	Abbosh C, Birkbak NJ, Wilson GA, et al. Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution[J] Nature, 2017, 545(7655):446-451. DOI: 10.1038/nature22364. doi: 10.1038/nature22364
[39]	Tucci M, Passarelli A, Mannavola F, et al. Serum exosomes as predictors of clinical response to ipilimumab in metastatic melanoma Oncoimmunology, 2017, 7(2):e1387706. DOI: 10.1080/2162402X.2017.1387706.
[40]	Syn NL, Wang L, Chow EK, et al. Exosomes in cancer nanomedicine and immunotherapy: prospects and challenges[J]. Trends Biotechnol, 2017, 35(7):665-676. DOI: 10.1016/j.tibtech.2017.03.004. doi: 10.1016/j.tibtech.2017.03.004
[41]	McKendry RT, Spalluto CM, Burke H, et al. Dysregulation of antiviral function of CD8(+) T cells in the chronic obstructive pulmonary disease lung. Role of the PD-1-PD-L1 axis[J]. Am J Respir Crit Care Med, 2016, 193(6):642-651. DOI: 10.1164/rccm.201504-0782OC. doi: 10.1164/rccm.201504-0782OC
[42]	Biton J, Ouakrim H, Dechartres A, et al. Impaired tumor-infiltrating T cells in patients with COPD impacts lung cancer response to PD-1 blockade[J]. Am J Respir Crit Care Med, 2018, 198(7):928-940. DOI: 10.1164/rccm.201706-1110OC. doi: 10.1164/rccm.201706-1110OC
[43]	Yi M, Yu S, Qin S, et al. Gut microbiome modulates efficacy of immune checkpoint inhibitors[J]. J Hematol Oncol, 2018, 11(1):47. DOI: 10.1186/s13045-018-0592-6. doi: 10.1186/s13045-018-0592-6
[44]	Matson V, Fessler J, Bao R, et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients[J]. Science, 2018, 359(6371):104-108. DOI: 10.1126/science.aao3290. doi: 10.1126/science.aao3290