免疫检查点抑制剂治疗结直肠癌生物标志物的研究进展
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摘要
免疫检查点抑制剂(immune checkpoint inhibitors,ICI)在多种晚期实体瘤治疗中取得了较好的临床疗效,其中包括结直肠癌。但是大多数的肿瘤患者对ICI象。寻找预测免疫治疗疗效的生物标志物,筛选出合适的人群至关重要。目前有多种生物标志物在预测ICI显示出指导价值,但最优的标志物仍未确定,需要进一步的大规模前瞻性研究证实潜在标志物的价值。本文将对免疫检查点抑制剂治疗结直肠癌的正性和负性生物标志物的研究进展进行综述。
Immune checkpoint inhibitors(ICI) show surprising clinical responses in various malignancies, including colorectal cancer. However,considerable number of cancer patients displayed an unsatisfactory objective response rate(ORR) to the immune checkpoint inhibitors.Treatment resistance is a common feature and hyperprogression was noticed in some patients. It is important to discover biomarkers which can predict the efficacy of immunotherapy and help in screening the suitable patients. Biomarkers have shown value in predicting the efficacy of immune checkpoint inhibitors in colorectal cancer treatment, however, the optimal biomarkers still remain undiscovered. Large-scale prospective studies are required to confirm the value of the potential biomarkers in future. This article reviews the reported predictive biomarkers with positive and negative response to immune checkpoint inhibitors in colorectal cancer.
Immune checkpoint inhibitors(ICI) show surprising clinical responses in various malignancies, including colorectal cancer. However,considerable number of cancer patients displayed an unsatisfactory objective response rate(ORR) to the immune checkpoint inhibitors.Treatment resistance is a common feature and hyperprogression was noticed in some patients. It is important to discover biomarkers which can predict the efficacy of immunotherapy and help in screening the suitable patients. Biomarkers have shown value in predicting the efficacy of immune checkpoint inhibitors in colorectal cancer treatment, however, the optimal biomarkers still remain undiscovered. Large-scale prospective studies are required to confirm the value of the potential biomarkers in future. This article reviews the reported predictive biomarkers with positive and negative response to immune checkpoint inhibitors in colorectal cancer.
引文
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[8]Schwitalle Y,Kloor M,Eiermann S,et al.Immune response against frameshift-induced neopeptides in HNPCC patients and healthy HNPCC mutation carriers[J].Gastroenterology,2008,134(4):988-997.
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[10]Koopman M,Kortman GA,Mekenkamp L,et al.Deficient mismatch repair system in patients with sporadic advanced colorectal cancer[J].Br J Cancer,2009,100(2):266-273.
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[12]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.
[13]Yarchoan M,Hopkins A,Jaffee EM.Tumor mutational burden and response rate to PD-1 inhibition[J].N Engl J Med,2017,377(25):2500-2501.
[14]Shien K,Papadimitrakopoulou VA,Wistuba II.Predictive biomarkers of response to PD-1/PD-L1 immune checkpoint inhibitors in non-small cell lung cancer[J].Lung Cancer,2016,99:79-87.
[15]Schumacher TN,Schreiber RD.Neoantigens in cancer immunotherapy[J].Science,2015,348(6230):69-74.
[16]Angelova M,Charoentong P,Hackl H,et al.Characterization of the immunophenotypes and antigenomes of colorectal cancers reveals distinct tumor escape mechanisms and novel targets for immunotherapy[J].Genome Biol,2015,16:64.
[17]Giannakis M,Mu XJ,Shukla SA,et al.Genomic correlates of immunecell infiltrates in colorectal carcinoma[J].Cell Rep,2016,15(4):857-865.
[18]Chowell D,Morris LGT,Grigg CM,et al.Patient HLA class I genotype influences cancer response to checkpoint blockade immunotherapy[J].Science,2018,359(6375):582-587.
[19]Carbognin L,Pilotto S,Milella M,et al.Differential activity of nivolumab,pembrolizumab and MPDL3280A according to the tumor expression of programmed death-ligand-1(PD-L1):sensitivity analysis of trials in melanoma,lung and genitourinary cancers[J].PLoS One,2015,10(6):e0130142.
[20]Taube JM,Klein A,Brahmer JR,et al.Association of PD-1,PD-1 ligands,and other features of the tumor immune microenvironment with response to anti-PD-1 therapy[J].Clin Cancer Res,2014,20(19):5064-5074.
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[22]Shi SJ,Wang LJ,Wang GD,et al.B7-H1 expression is associated with poor prognosis in colorectal carcinoma and regulates the proliferation and invasion of HCT116 colorectal cancer cells[J].PLoS One,2013,8(10):e76012.
[23]Liang M,Li J,Wang D,et al.T-cell infiltration and expressions of Tlymphocyte co-inhibitory B7-H1 and B7-H4 molecules among colorectal cancer patients in northeast China's Heilongjiang province[J].Tumour Biol,2014,35(1):55-60.
[24]Nebot-Bral L,Brandao D,Verlingue L,et al.Hypermutated tumours in the era of immunotherapy:The paradigm of personalised medicine[J].Eur J Cancer,2017,84:290-303.
[25]Bourdais R,Rousseau B,Pujals A,et al.Polymerase proofreading domain mutations:New opportunities for immunotherapy in hypermutated colorectal cancer beyond MMR deficiency[J].Crit Rev Oncol Hematol,2017,113:242-248.
[26]Domingo E,Freeman-Mills L,Rayner E,et al.Somatic POLE proofreading domain mutation,immune response,and prognosis in colorectal cancer:a retrospective,pooled biomarker study[J].Lancet Gastroenterol Hepatol,2016,1(3):207-216.
[27]Glaire MA,Domingo E,Vermeulen L,et al.POLE proofreading domain mutation defines a subset of immunogenic colorectal cancers with excellent prognosis[J].Ann Oncol,2016,27(suppl_6):4600.
[28]Rayner E,van Gool IC,Palles C,et al.A panoply of errors:polymerase proofreading domain mutations in cancer[J].Nat Rev Cancer,2016,16(2):71-81.
[29]Champiat S,Dercle L,Ammari S,et al.Hyperprogressive disease is a new pattern of progression in cancer patients treated by anti-PD-1/PD-L1[J].Clin Cancer Res,2017,23(8):1920-1928.
[30]Saada-Bouzid E,Defaucheux C,Karabajakian A,et al.Hyperprogression during anti-PD-1/PD-L1 therapy in patients with recurrent and/or metastatic head and neck squamous cell carcinoma[J].Ann Oncol,2017,28(7):1605-1611.
[31]Borghaei H,Paz-Ares L,Horn L,et al.Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer[J].N Engl J Med,2015,373(17):1627-1639.
[32]Landre T,Taleb C,Nicolas P,et al.Is there a clinical benefit of anti-PD-1 in patients older than 75 years with previously treated solid tumour[J]?J Clin Oncol,2016,34(15_suppl):3070.
[33]Motzer RJ,Escudier B,McDermott DF,et al.Nivolumab versus everolimus in advanced renal-cell carcinoma[J].N Engl J Med,2015,373(19):1803-1813.
[34]Singavi AK,Menon S,Kilari D,et al.Predictive biomarkers for hyperprogression(HP)in response to immune checkpoint inhibitors(ICI)-analysis of somatic alterations(SAs)[J].Ann Oncol,2017,28(suppl_5):405.
[35]Elinav E,Nowarski R,Thaiss CA,et al.Inflammation-induced cancer:crosstalk between tumours,immune cells and microorganisms[J].Nat Rev Cancer,2013,13(11):759-771.
[36]Jiang T,Qiao M,Zhao C,et al.Pretreatment neutrophil-to-lymphocyte ratio is associated with outcome of advanced-stage cancer patients treated with immunotherapy:a meta-analysis[J].Cancer Immunol Immunother,2018,67(5):713-727.
[37]Sacdalan DB,Lucero JA,Sacdalan DL.Prognostic utility of baseline neutrophil-to-lymphocyte ratio in patients receiving immune checkpoint inhibitors:a review and meta-analysis[J].Onco Targets Ther,2018,11:955-965.
[38]Ferrucci PF,Ascierto PA,Pigozzo J,et al.Baseline neutrophils and derived neutrophil-to-lymphocyte ratio:prognostic relevance in metastatic melanoma patients receiving ipilimumab[J].Ann Oncol,2016,27(4):732-738.
[39]Petrelli F,Cabiddu M,Coinu A,et al.Prognostic role of lactate dehydrogenase in solid tumors:a systematic review and meta-analysis of76 studies[J].Acta Oncol,2015,54(7):961-970.
[40]Weide B,Martens A,Hassel JC,et al.Baseline biomarkers for outcome of melanoma patients treated with pembrolizumab[J].Clin Cancer Res,2016,22(22):5487-5496.
[41]Conforti F,Pala L,Bagnardi V,et al.Cancer immunotherapy efficacy and patients'sex:a systematic review and meta-analysis[J].Lancet Oncol,2018,19(6):737-746.
[42]Schreiber RD,Old LJ,Smyth MJ.Cancer immunoediting:integrating immunity's roles in cancer suppression and promotion[J].Science,2011,331(6024):1565-1570.
[43]Wang GZ,Zhang L,Zhao XC,et al.The Aryl hydrocarbon receptor mediates tobacco-induced PD-L1 expression and is associated with response to immunotherapy[J].Nat Commun,2019,10:1125.
[44]Albacker LA,Wu J,Smith P,et al.Loss of function JAK1 mutations occur at high frequency in cancers with microsatellite instability and are suggestive of immune evasion[J].PLoS One,2017,12(11):e0176181.
[45]Shin DS,Zaretsky JM,Escuin-Ordinas H,et al.Primary resistance to pd-1 blockade mediated by JAK1/2 mutations[J].Cancer Discov,2017,7(2):188-201.
[2]Hochster HS,Bendell JC,Cleary JM,et al.Efficacy and safety of atezolizumab(atezo)and bevacizumab(bev)in a phase Ib study of microsatellite instability(MSI)-high metastatic colorectal cancer(mCRC)[J].J Clin Oncol,2017,35(4_suppl):673-673.
[3]Le DT,Uram JN,Wang H,et al.PD-1 blockade in tumors with mismatchrepair deficiency[J].N Engl J Med,2015,372(26):2509-2520.
[4]Brahmer J,Reckamp KL,Baas P,et al.Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer[J].N Engl J Med,2015,373(2):123-135.
[5]Zaretsky JM,Garcia-Diaz A,Shin DS,et al.Mutations associated with acquired resistance to PD-1 blockade in melanoma[J].N Engl J Med,2016,375(9):819-829.
[6]Gao J,Shi LZ,Zhao H,et al.Loss of IFN-gamma pathway genes in tumor cells as a mechanism of resistance to Anti-CTLA-4 therapy[J].Cell,2016,167(2):397-404.
[7]Kato S,Goodman A,Walavalkar V,et al.Hyperprogressors after immunotherapy:analysis of genomic alterations associated with accelerated growth rate[J].Clin Cancer Res,2017,23(15):4242-4250.
[8]Schwitalle Y,Kloor M,Eiermann S,et al.Immune response against frameshift-induced neopeptides in HNPCC patients and healthy HNPCC mutation carriers[J].Gastroenterology,2008,134(4):988-997.
[9]Pawlik TM,Raut CP,Rodriguez-Bigas MA.Colorectal carcinogenesis:MSI-H versus MSI-L[J].Dis Markers,2004,20(4-5):199-206.
[10]Koopman M,Kortman GA,Mekenkamp L,et al.Deficient mismatch repair system in patients with sporadic advanced colorectal cancer[J].Br J Cancer,2009,100(2):266-273.
[11]Rizvi NA,Hellmann MD,Snyder A,et al.Cancer immunology.Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer[J].Science,2015,348(6230):124-128.
[12]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.
[13]Yarchoan M,Hopkins A,Jaffee EM.Tumor mutational burden and response rate to PD-1 inhibition[J].N Engl J Med,2017,377(25):2500-2501.
[14]Shien K,Papadimitrakopoulou VA,Wistuba II.Predictive biomarkers of response to PD-1/PD-L1 immune checkpoint inhibitors in non-small cell lung cancer[J].Lung Cancer,2016,99:79-87.
[15]Schumacher TN,Schreiber RD.Neoantigens in cancer immunotherapy[J].Science,2015,348(6230):69-74.
[16]Angelova M,Charoentong P,Hackl H,et al.Characterization of the immunophenotypes and antigenomes of colorectal cancers reveals distinct tumor escape mechanisms and novel targets for immunotherapy[J].Genome Biol,2015,16:64.
[17]Giannakis M,Mu XJ,Shukla SA,et al.Genomic correlates of immunecell infiltrates in colorectal carcinoma[J].Cell Rep,2016,15(4):857-865.
[18]Chowell D,Morris LGT,Grigg CM,et al.Patient HLA class I genotype influences cancer response to checkpoint blockade immunotherapy[J].Science,2018,359(6375):582-587.
[19]Carbognin L,Pilotto S,Milella M,et al.Differential activity of nivolumab,pembrolizumab and MPDL3280A according to the tumor expression of programmed death-ligand-1(PD-L1):sensitivity analysis of trials in melanoma,lung and genitourinary cancers[J].PLoS One,2015,10(6):e0130142.
[20]Taube JM,Klein A,Brahmer JR,et al.Association of PD-1,PD-1 ligands,and other features of the tumor immune microenvironment with response to anti-PD-1 therapy[J].Clin Cancer Res,2014,20(19):5064-5074.
[21]Droeser RA,Hirt C,Viehl CT,et al.Clinical impact of programmed cell death ligand 1 expression in colorectal cancer[J].Eur J Cancer,2013,49(9):2233-2242.
[22]Shi SJ,Wang LJ,Wang GD,et al.B7-H1 expression is associated with poor prognosis in colorectal carcinoma and regulates the proliferation and invasion of HCT116 colorectal cancer cells[J].PLoS One,2013,8(10):e76012.
[23]Liang M,Li J,Wang D,et al.T-cell infiltration and expressions of Tlymphocyte co-inhibitory B7-H1 and B7-H4 molecules among colorectal cancer patients in northeast China's Heilongjiang province[J].Tumour Biol,2014,35(1):55-60.
[24]Nebot-Bral L,Brandao D,Verlingue L,et al.Hypermutated tumours in the era of immunotherapy:The paradigm of personalised medicine[J].Eur J Cancer,2017,84:290-303.
[25]Bourdais R,Rousseau B,Pujals A,et al.Polymerase proofreading domain mutations:New opportunities for immunotherapy in hypermutated colorectal cancer beyond MMR deficiency[J].Crit Rev Oncol Hematol,2017,113:242-248.
[26]Domingo E,Freeman-Mills L,Rayner E,et al.Somatic POLE proofreading domain mutation,immune response,and prognosis in colorectal cancer:a retrospective,pooled biomarker study[J].Lancet Gastroenterol Hepatol,2016,1(3):207-216.
[27]Glaire MA,Domingo E,Vermeulen L,et al.POLE proofreading domain mutation defines a subset of immunogenic colorectal cancers with excellent prognosis[J].Ann Oncol,2016,27(suppl_6):4600.
[28]Rayner E,van Gool IC,Palles C,et al.A panoply of errors:polymerase proofreading domain mutations in cancer[J].Nat Rev Cancer,2016,16(2):71-81.
[29]Champiat S,Dercle L,Ammari S,et al.Hyperprogressive disease is a new pattern of progression in cancer patients treated by anti-PD-1/PD-L1[J].Clin Cancer Res,2017,23(8):1920-1928.
[30]Saada-Bouzid E,Defaucheux C,Karabajakian A,et al.Hyperprogression during anti-PD-1/PD-L1 therapy in patients with recurrent and/or metastatic head and neck squamous cell carcinoma[J].Ann Oncol,2017,28(7):1605-1611.
[31]Borghaei H,Paz-Ares L,Horn L,et al.Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer[J].N Engl J Med,2015,373(17):1627-1639.
[32]Landre T,Taleb C,Nicolas P,et al.Is there a clinical benefit of anti-PD-1 in patients older than 75 years with previously treated solid tumour[J]?J Clin Oncol,2016,34(15_suppl):3070.
[33]Motzer RJ,Escudier B,McDermott DF,et al.Nivolumab versus everolimus in advanced renal-cell carcinoma[J].N Engl J Med,2015,373(19):1803-1813.
[34]Singavi AK,Menon S,Kilari D,et al.Predictive biomarkers for hyperprogression(HP)in response to immune checkpoint inhibitors(ICI)-analysis of somatic alterations(SAs)[J].Ann Oncol,2017,28(suppl_5):405.
[35]Elinav E,Nowarski R,Thaiss CA,et al.Inflammation-induced cancer:crosstalk between tumours,immune cells and microorganisms[J].Nat Rev Cancer,2013,13(11):759-771.
[36]Jiang T,Qiao M,Zhao C,et al.Pretreatment neutrophil-to-lymphocyte ratio is associated with outcome of advanced-stage cancer patients treated with immunotherapy:a meta-analysis[J].Cancer Immunol Immunother,2018,67(5):713-727.
[37]Sacdalan DB,Lucero JA,Sacdalan DL.Prognostic utility of baseline neutrophil-to-lymphocyte ratio in patients receiving immune checkpoint inhibitors:a review and meta-analysis[J].Onco Targets Ther,2018,11:955-965.
[38]Ferrucci PF,Ascierto PA,Pigozzo J,et al.Baseline neutrophils and derived neutrophil-to-lymphocyte ratio:prognostic relevance in metastatic melanoma patients receiving ipilimumab[J].Ann Oncol,2016,27(4):732-738.
[39]Petrelli F,Cabiddu M,Coinu A,et al.Prognostic role of lactate dehydrogenase in solid tumors:a systematic review and meta-analysis of76 studies[J].Acta Oncol,2015,54(7):961-970.
[40]Weide B,Martens A,Hassel JC,et al.Baseline biomarkers for outcome of melanoma patients treated with pembrolizumab[J].Clin Cancer Res,2016,22(22):5487-5496.
[41]Conforti F,Pala L,Bagnardi V,et al.Cancer immunotherapy efficacy and patients'sex:a systematic review and meta-analysis[J].Lancet Oncol,2018,19(6):737-746.
[42]Schreiber RD,Old LJ,Smyth MJ.Cancer immunoediting:integrating immunity's roles in cancer suppression and promotion[J].Science,2011,331(6024):1565-1570.
[43]Wang GZ,Zhang L,Zhao XC,et al.The Aryl hydrocarbon receptor mediates tobacco-induced PD-L1 expression and is associated with response to immunotherapy[J].Nat Commun,2019,10:1125.
[44]Albacker LA,Wu J,Smith P,et al.Loss of function JAK1 mutations occur at high frequency in cancers with microsatellite instability and are suggestive of immune evasion[J].PLoS One,2017,12(11):e0176181.
[45]Shin DS,Zaretsky JM,Escuin-Ordinas H,et al.Primary resistance to pd-1 blockade mediated by JAK1/2 mutations[J].Cancer Discov,2017,7(2):188-201.