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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front. Med.    2019, Vol. 13 Issue (1) : 24-31
Screening responsive or resistant biomarkers of immune checkpoint inhibitors based on online databases
Zhen Xiang, Yingyan Yu()
Department of Surgery, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine; Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
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Immune checkpoint inhibitors are a promising strategy in the treatment of cancer, especially advanced types. However, not all patients are responsive to immune checkpoint inhibitors. The response rate depends on the immune microenvironment, tumor mutational burden (TMB), expression level of immune checkpoint proteins, and molecular subtypes of cancers. Along with the Cancer Genome Project, various open access databases, including The Cancer Genome Atlas and Gene Expression Omnibus, provide large volumes of data, which allow researchers to explore responsive or resistant biomarkers of immune checkpoint inhibitors. In this review, we introduced some methodologies on database selection, biomarker screening, current progress of immune checkpoint blockade in solid tumor treatment, possible mechanisms of drug resistance, strategies of overcoming resistance, and indications for immune checkpoint inhibitor therapy.

Keywords immune checkpoint blockade      sensitivity      resistance      data mining     
Corresponding Authors: Yingyan Yu   
Just Accepted Date: 28 December 2018   Online First Date: 18 January 2019    Issue Date: 12 March 2019
 Cite this article:   
Zhen Xiang,Yingyan Yu. Screening responsive or resistant biomarkers of immune checkpoint inhibitors based on online databases[J]. Front. Med., 2019, 13(1): 24-31.
Fig.1  Immune checkpoint inhibitors approved by the FDA. From left to right, the six immune checkpoint inhibitors are listed. Ipilimumab targets CTLA-4. Pembrolizumab and nivolumab target PD-1. Atezolizumab, avelumab, and durvalumab target PD-L1. The drugs are presented according to the chronological order of FDA approval.
Drug name Trade name Target Structure Company Indications
Ipilimumab Yervoy CTLA-4 IgG1 Bristol-Myers Squibb Unresectable or metastatic melanoma (first or second line)
Stage III cutaneous melanoma (adjuvant therapy, first line)
Pembrolizumab Keytruda PD-1 IgG4 Bristol-Myers Squibb Unresectable or metastatic melanoma (first line)
Metastatic non-small cell lung cancer (TPS*≥1%, second line; TPS≥50%, first line)
Recurrent or metastatic head and neck squamous cell carcinoma (second line)
Refractory classical Hodgkin lymphoma (second or more lines)
Metastatic nonsquamous non-small cell lung cancer (plus pemetrexed and carboplatin, first line)
Locally advanced or metastatic urothelial carcinoma (second line)
Unresectable or metastatic solid tumor with high MSI (second line). Advanced gastric cancer (second line)
Nivolumab Opdivo PD-1 IgG4 MSD Unresectable or metastatic melanoma (alone or with ipilimumab, second line)
Metastatic squamous non-small cell lung cancer (second line or third line)
Renal cell carcinoma (second line)
Classical Hodgkin lymphoma (second line)
Adult classical Hodgkin lymphoma (second or more lines)
Recurrent or metastatic squamous cell carcinoma of the head and neck (second line)
Locally advanced or metastatic urothelial carcinoma (second line)
Unresectable or metastatic solid tumor with high MSI (second line). Hepatocellular carcinoma (second or more lines)
Atezolizumab Tecentriq PD-L1 IgG1 Roche Locally advanced or metastatic urothelial carcinoma (second line)
Metastatic non-small cell lung cancer (second line)
Avelumab Bavencio PD-L1 IgG1 Pfizer/MERCK Adult and pediatric metastatic Merkel cell carcinoma in patients (second line)
Locally advanced or metastatic urothelial carcinoma (second line)
Durvalumab Imfinzi PD-L1 IgG1 AstraZeneca Locally advanced or metastatic urothelial carcinoma (second line)
Unresectable stage III non-small cell lung cancer (second line)
Tab.1  Immune checkpoint inhibitors approved by the FDA (
Fig.2  Analytical flowchart of data mining for transcriptomic data from GEO and TCGA databases. All data are processed by different packages of R software. Step 1: Affy package (rma method); step 2: Sva package; step 3: survival package; step 4: Limma package; step 5: edgeR package; step 6: GSEA software; step 7: WGCNA package; step 8: ConsensusClusterPlus package; step 9: pheatmap package; step 10: ClusterProfiler package; step 11: Rbsurv package (model with minimal AIC); step 12: Cytoscape software; step 13: glmnet package (Lasso regression). GEO: gene expression omnibus; GSEA: Gene Set Enrichment Analysis; WGCNA: weighted gene co-expression network analysis; GO: Gene Ontology; DEGs: differentially expressed genes.
1 NLonberg, AJ Korman. Masterful antibodies: checkpoint blockade. Cancer Immunol Res 2017; 5(4): 275–281 pmid: 28373215
2 XZhao, S Subramanian. Intrinsic resistance of solid tumors to immune checkpoint blockade therapy. Cancer Res 2017; 77(4): 817–822 pmid: 28159861
3 PSharma, JP Allison. The future of immune checkpoint therapy. Science 2015; 348(6230): 56–61 pmid: 25838373
4 LChen, X Han. Anti-PD-1/PD-L1 therapy of human cancer: past, present, and future. J Clin Invest 2015; 125(9): 3384–3391 pmid: 26325035
5 AGoodman, SP Patel, RKurzrock. PD-1-PD-L1 immune-checkpoint blockade in B-cell lymphomas. Nat Rev Clin Oncol 2017; 14(4): 203–220 pmid: 27805626
6 GVarricchi, MR Galdiero, GMarone, GCriscuolo, MTriassi, DBonaduce, GMarone, CGTocchetti. Cardiotoxicity of immune checkpoint inhibitors. ESMO Open 2017; 2(4): e000247 pmid: 29104763
7 CBrignone, M Gutierrez, FMefti, EBrain, RJarcau, FCvitkovic, NBousetta, JMedioni, JGligorov, CGrygar, MMarcu, FTriebel. First-line chemoimmunotherapy in metastatic breast carcinoma: combination of paclitaxel and IMP321 (LAG-3Ig) enhances immune responses and antitumor activity. J Transl Med 2010; 8(1): 71 pmid: 20653948
8 ALegat, H Maby-El Hajjami, PBaumgaertner, LCagnon, SAbed Maillard, CGeldhof, EMIancu, LLebon, PGuillaume, DDojcinovic, OMichielin, ERomano, GBerthod, DRimoldi, FTriebel, ILuescher, NRufer, DESpeiser. Vaccination with LAG-3Ig (IMP321) and peptides induces specific CD4 and CD8 T-cell responses in metastatic melanoma patients—report of a phase I/IIa clinical trial. Clin Cancer Res 2016; 22(6): 1330–1340 pmid: 26500235
9 HHSoliman, SE Minton, HSHan, RIsmail-Khan, ANeuger, FKhambati, DNoyes, RLush, AA Chiappori, JDRoberts, CLink, NN Vahanian, MMautino, HStreicher, DMSullivan, SJAntonia. A phase I study of indoximod in patients with advanced malignancies. Oncotarget 2016; 7(16): 22928–22938 pmid: 27008709
10 NHSegal, TF Logan, FSHodi, DMcDermott, IMelero, OHamid, HSchmidt, CRobert, VChiarion-Sileni, PAAscierto, MMaio, WJ Urba, TCGangadhar, SSuryawanshi, JNeely, MJure-Kunkel, SKrishnan, HKohrt, MSznol, RLevy. Results from an integrated safety analysis of urelumab, an agonist anti-CD137 monoclonal antibody. Clin Cancer Res 2017; 23(8): 1929–1936 pmid: 27756788
11 HLäubli, P Müller, LD’Amico, MBuchi, ASKashyap, AZippelius. The multi-receptor inhibitor axitinib reverses tumor-induced immunosuppression and potentiates treatment with immune-modulatory antibodies in preclinical murine models. Cancer Immunol Immunother 2018; 67(5): 815–824 pmid: 29487979
12 DASchaer, RP Beckmann, JADempsey, LHuber, AForest, NAmaladas, YLi, YC Wang, ERRasmussen, DChin, A Capen, CCarpenito, KAStaschke, LAChung, LMLitchfield, FFMerzoug, XGong, PW Iversen, SBuchanan, Ade Dios, RDNovosiadly, MKalos. The CDK4/6 inhibitor abemaciclib induces a T cell inflamed tumor microenvironment and enhances the efficacy of PD-L1 checkpoint blockade. Cell Rep 2018; 22(11): 2978–2994 pmid: 29539425
13 MFKrummel, JP Allison. CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J Exp Med 1995; 182(2): 459–465 pmid: 7543139
14 JMPitt, M Vétizou, RDaillère, MPRoberti, TYamazaki, BRouty, PLepage, IGBoneca, MChamaillard, GKroemer, LZitvogel. Resistance mechanisms to immune-checkpoint blockade in cancer: tumor-intrinsic and-extrinsic factors. Immunity 2016; 44(6): 1255–1269 pmid: 27332730
15 TRSimpson, F Li, WMontalvo-Ortiz, MASepulveda, KBergerhoff, FArce, C Roddie, JYHenry, HYagita, JDWolchok, KSPeggs, JVRavetch, JPAllison, SAQuezada. Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma. J Exp Med 2013; 210(9): 1695–1710 pmid: 23897981
16 GJFreeman, AJ Long, YIwai, KBourque, TChernova, HNishimura, LJFitz, NMalenkovich, TOkazaki, MCByrne, HFHorton, LFouser, LCarter, VLing, MR Bowman, BMCarreno, MCollins, CRWood, THonjo. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 2000; 192(7): 1027–1034 pmid: 11015443
17 DMPardoll. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012; 12(4): 252–264 pmid: 22437870
18 ATunger, M Kießler, RWehner, ATemme, FMeier, MBachmann, MSchmitz. Immune monitoring of cancer patients prior to and during CTLA-4 or PD-1/PD-L1 inhibitor treatment. Biomedicines 2018; 6(1): E26 pmid: 29494517
19 XXing, J Guo, XWen, GDing, B Li, BDong, QFeng, S Li, JZhang, XCheng, TGuo, H Du, YHu, XWang, L Li, QLi, MXie, L Li, XGao, FShan, Z Li, XYing, TZhou, J Wang, JJi. Analysis of PD1, PDL1, PDL2 expression and T cells infiltration in 1014 gastric cancer patients. Oncoimmunology 2017; 7(3): e1356144 pmid: 29399387
20 [] CWLi, SO Lim, EMChung, YSKim, AH Park, JYao, JHCha, W Xia, LCChan, TKim, SS Chang, HHLee, CKChou, YLLiu, HC Yeh, EPPerillo, AKDunn, CWKuo, KH Khoo, JLHsu, YWu, JM Hsu, HYamaguchi, THHuang, AASahin, GNHortobagyi, SSYoo, MC Hung. Eradication of triple-negative breast cancer cells by targeting glycosylated PD-L1. Cancer Cell 2018; 33(2): 187–201.e10
21 SKorehisa, E Oki, MIimori, YNakaji, MShimokawa, HSaeki, SOkano, YOda, Y Maehara. Clinical significance of programmed cell death-ligand 1 expression and the immune microenvironment at the invasive front of colorectal cancers with high microsatellite instability. Int J Cancer 2018; 142(4): 822–832 pmid: 29044503
22 WZou, JD Wolchok, LChen. PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: mechanisms, response biomarkers, and combinations. Sci Transl Med 2016; 8(328): 328rv4 pmid: 26936508
23 MJButte, ME Keir, TBPhamduy, AHSharpe, GJFreeman. Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity 2007; 27(1): 111–122 pmid: 17629517
24 JJPark, R Omiya, YMatsumura, YSakoda, AKuramasu, MMAugustine, SYao, F Tsushima, HNarazaki, SAnand, YLiu, SE Strome, LChen, KTamada. B7-H1/CD80 interaction is required for the induction and maintenance of peripheral T-cell tolerance. Blood 2010; 116(8): 1291–1298 pmid: 20472828
25 BCao, Q Wang, HZhang, GZhu, J Lang. Two immune-enhanced molecular subtypes differ in inflammation, checkpoint signaling and outcome of advanced head and neck squamous cell carcinoma. Oncoimmunology 2017; 7(2): e1392427 pmid: 29308323
26 DLuo, B Deng, MWeng, ZLuo, X Nie. A prognostic 4-lncRNA expression signature for lung squamous cell carcinoma. Artif Cells Nanomed Biotechnol 2018; 46(6): 1207–1214 pmid: 28835135
27 XMao, X Qin, LLi, JZhou, M Zhou, XLi, YXu, L Yuan, QNLiu, HXing. A 15-long non-coding RNA signature to improve prognosis prediction of cervical squamous cell carcinoma. Gynecol Oncol 2018; 149(1): 181–187 pmid: 29525275
28 AATarhini, Y Lin, HMLin, PVallabhaneni, CSander, WLaFramboise, LHamieh. Expression profiles of immune-related genes are associated with neoadjuvant ipilimumab clinical benefit. Oncoimmunology 2016; 6(2): e1231291 pmid: 28344862
29 CPark, J Cho, JLee, SYKang, JYAn, MG Choi, JHLee, TSSohn, JMBae, S Kim, STKim, SHPark, JOPark, WKKang, ISohn, SH Jung, MSKang, KMKim. Host immune response index in gastric cancer identified by comprehensive analyses of tumor immunity. Oncoimmunology 2017; 6(11): e1356150 pmid: 29147610
30 PWu, JL Liu, SMPei, CPWu, K Yang, SPWang, SWu. Integrated genomic analysis identifies clinically relevant subtypes of renal clear cell carcinoma. BMC Cancer 2018; 18(1): 287 pmid: 29534679
31 WEJohnson, C Li, ARabinovic. Adjusting batch effects in microarray expression data using empirical Bayes methods. Biostatistics 2007; 8(1): 118–127 pmid: 16632515
32 PKupfer, R Guthke, DPohlers, RHuber, DKoczan, RWKinne. Batch correction of microarray data substantially improves the identification of genes differentially expressed in rheumatoid arthritis and osteoarthritis. BMC Med Genomics 2012; 5(1): 23 pmid: 22682473
33 RTian, X Li, YGao, YLi, P Yang, KWang. Identification and validation of the role of matrix metalloproteinase-1 in cervical cancer. Int J Oncol 2018; 52(4): 1198–1208 pmid: 29436615
34 JYHou, YG Wang, SJMa, BYYang, QPLi. Identification of a prognostic 5-Gene expression signature for gastric cancer. J Cancer Res Clin Oncol 2017; 143(4): 619–629 pmid: 28035468
35 FFiorica, L Belluomini, AStefanelli, ASantini, BUrbini, CGiorgi, AFrassoldati. Immune checkpoint inhibitor nivolumab and radiotherapy in pretreated lung cancer patients: efficacy and safety of combination. Am J Clin Oncol 2018 Jan 31. [Epub ahead of print] doi:10.1097/COC.0000000000000428
pmid: 29389733
36 CFeig, JO Jones, MKraman, RJWells, ADeonarine, DSChan, CMConnell, EWRoberts, QZhao, OL Caballero, SATeichmann, TJanowitz, DIJodrell, DATuveson, DTFearon. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc Natl Acad Sci U S A 2013; 110(50): 20212–20217 pmid: 24277834
37 KKim, AD Skora, ZLi, QLiu, AJ Tam, RLBlosser, LADiaz Jr, NPapadopoulos, KWKinzler, BVogelstein, SZhou. Eradication of metastatic mouse cancers resistant to immune checkpoint blockade by suppression of myeloid-derived cells. Proc Natl Acad Sci U S A 2014; 111(32): 11774–11779 pmid: 25071169
38 KGanesh, J Massagué. TGF-b inhibition and immunotherapy: checkmate. Immunity 2018; 48(4): 626–628 pmid: 29669246
39 MTariq, J Zhang, GLiang, LDing, Q He, BYang. Macrophage polarization: anti-cancer strategies to target tumor-associated macrophage in breast cancer. J Cell Biochem 2017; 118(9): 2484–2501 pmid: 28106295
40 MDe Palma, CE Lewis. Macrophage regulation of tumor responses to anticancer therapies. Cancer Cell 2013; 23(3): 277–286 pmid: 23518347
41 WYao, Q Ba, XLi, HLi, S Zhang, YYuan, FWang, X Duan, JLi, WZhang, HWang. A natural CCR2 antagonist relieves tumor-associated macrophage-mediated immunosuppression to produce a therapeutic effect for liver cancer. EBioMedicine 2017; 22: 58–67 pmid: 28754304
42 KHarada, X Dong, JSEstrella, AMCorrea, YXu, WL Hofstetter, KSudo, HOnodera, KSuzuki, ASuzuki, RLJohnson, ZWang, S Song, JAAjani. Tumor-associated macrophage infiltration is highly associated with PD-L1 expression in gastric adenocarcinoma. Gastric Cancer 2018; 21(1): 31–40 pmid: 28801853
43 ECerami, J Gao, UDogrusoz, BEGross, SOSumer, BAAksoy, AJacobsen, CJByrne, MLHeuer, ELarsson, YAntipin, BReva, AP Goldberg, CSander, NSchultz. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov 2012; 2(5): 401–404 pmid: 22588877
44 WHugo, JM Zaretsky, LSun, CSong, BH Moreno, SHu-Lieskovan, BBerent-Maoz, JPang, B Chmielowski, GCherry, ESeja, S Lomeli, XKong, MCKelley, JASosman, DBJohnson, ARibas, RSLo. Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma. Cell 2017; 168(3): 542 pmid: 28129544
45 APrat, A Navarro, LParé, NReguart, PGalván, TPascual, AMartínez, PNuciforo, LComerma, LAlos, N Pardo, SCedrés, CFan, JS Parker, LGaba, IVictoria, NViñolas, AVivancos, AArance, EFelip. Immune-related gene expression profiling after PD-1 blockade in non-small cell lung carcinoma, head and neck squamous cell carcinoma, and melanoma. Cancer Res 2017; 77(13): 3540–3550 pmid: 28487385
46 MLAscierto, TL McMiller, AEBerger, LDanilova, RAAnders, GJNetto, HXu, TS Pritchard, JFan, CCheadle, LCope, CG Drake, DMPardoll, JMTaube, SLTopalian. The intratumoral balance between metabolic and immunologic gene expression is associated with anti-PD-1 response in patients with renal cell carcinoma. Cancer Immunol Res 2016; 4(9): 726–733 pmid: 27491898
47 MLAscierto, A Makohon-Moore, EJLipson, JMTaube, TLMcMiller, AEBerger, JFan, GJ Kaunitz, TRCottrell, ZAKohutek, AFavorov, VMakarov, NRiaz, TA Chan, LCope, RHHruban, DMPardoll, BSTaylor, DBSolit, CAIacobuzio-Donahue, SLTopalian. Transcriptional mechanisms of resistance to anti-PD-1 therapy. Clin Cancer Res 2017; 23(12): 3168–3180 pmid: 28193624
48 YYJanjigian, F Sanchez-Vega, PJonsson, WKChatila, JFHechtman, GYKu, JC Riches, YTuvy, RKundra, NBouvier, EVakiani, JGao, ZJ Heins, BEGross, DPKelsen, LZhang, VEStrong, MSchattner, HGerdes, DGCoit, MBains, ZKStadler, VWRusch, DRJones, DMolena, JShia, ME Robson, MCapanu, SMiddha, AZehir, DMHyman, MScaltriti, MLadanyi, NRosen, DHIlson, MFBerger, LTang, BS Taylor, DBSolit, NSchultz. Genetic predictors of response to systemic therapy in esophagogastric cancer. Cancer Discov 2018; 8(1): 49–58 pmid: 29122777
49 KLGrogg, CM Lohse, VSPankratz, KCHalling, TCSmyrk. Lymphocyte-rich gastric cancer: associations with Epstein-Barr virus, microsatellite instability, histology, and survival. Mod Pathol 2003; 16(7): 641–651 pmid: 12861059
50 YYu. Molecular classification and precision therapy of cancer: immune checkpoint inhibitors. Front Med 2018; 12(2): 229–235 pmid: 29209918
51 MAPereira, MFKP Ramos, SFFaraj, ARDias, OKYagi, BZilberstein, ICecconello, VAFAlves, ESde Mello, URibeiro Jr. Clinicopathological and prognostic features of Epstein-Barr virus infection, microsatellite instability, and PD-L1 expression in gastric cancer. J Surg Oncol 2018; 117(5): 829–839 pmid: 29534305
52 XLiu, J Liu, HQiu, PKong, S Chen, WLi, YZhan, Y Li, YChen, ZZhou, D Xu, XSun. Prognostic significance of Epstein-Barr virus infection in gastric cancer: a meta-analysis. BMC Cancer 2015; 15(1): 782 pmid: 26498209
53 MLAscierto, TL McMiller, AEBerger, LDanilova, RAAnders, GJNetto, HXu, TS Pritchard, JFan, CCheadle, LCope, CG Drake, DMPardoll, JMTaube, SLTopalian. The intratumoral balance between metabolic and immunologic gene expression is associated with anti-PD-1 response in patients with renal cell carcinoma. Cancer Immunol Res 2016; 4(9): 726–733 pmid: 27491898
54 MLAscierto, A Makohon-Moore, EJLipson, JMTaube, TLMcMiller, AEBerger, JFan, GJ Kaunitz, TRCottrell, ZAKohutek, AFavorov, VMakarov, NRiaz, TA Chan, LCope, RHHruban, DMPardoll, BSTaylor, DBSolit, CAIacobuzio-Donahue, SLTopalian. Transcriptional mechanisms of resistance to anti-PD-1 therapy. Clin Cancer Res 2017; 23(12): 3168–3180 pmid: 28193624
55 DTLe, JN Durham, KNSmith, HWang, BR Bartlett, LKAulakh, SLu, H Kemberling, CWilt, BSLuber, FWong, NS Azad, AARucki, DLaheru, RDonehower, AZaheer, GAFisher, TSCrocenzi, JJLee, TF Greten, AGDuffy, KKCiombor, ADEyring, BHLam, A Joe, SPKang, MHoldhoff, LDanilova, LCope, C Meyer, SZhou, RMGoldberg, DKArmstrong, KMBever, ANFader, JTaube, FHousseau, DSpetzler, NXiao, DM Pardoll, NPapadopoulos, KWKinzler, JREshleman, BVogelstein, RAAnders, LADiaz Jr. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 2017; 357(6349): 409–413 pmid: 28596308
56 PDuconseil, J Périnel, AAutret, MAdham, ASauvanet, LChiche, JYMabrut, JJTuech, CMariette, NRégenet, JMFabre, PBachellier, JRDelpéro, FPaye, O Turrini. Resectable invasive IPMN versus sporadic pancreatic adenocarcinoma of the head of the pancreas: Should these two different diseases receive the same treatment? A matched comparison study of the French Surgical Association (AFC). Eur J Surg Oncol 2017; 43(9): 1704–1710 pmid: 28687431
57 NZhao, G Zheng, JLi, HYZhao, CLu, M Jiang, CZhang, HTGuo, AP Lu. Text mining of rheumatoid arthritis and diabetes mellitus to understand the mechanisms of Chinese medicine in different diseases with same treatment. Chin J Integr Med 2018; 24(10): 777–784 pmid: 29327123
58 GLBeatty, WL Gladney. Immune escape mechanisms as a guide for cancer immunotherapy. Clin Cancer Res 2015; 21(4): 687–692 pmid: 25501578
59 DSStraus. Somatic mutation, cellular differentiation, and cancer causation. J Natl Cancer Inst 1981; 67(2): 233–241
pmid: 7021938
60 EMVan Allen, D Miao, BSchilling, SAShukla, CBlank, LZimmer, ASucker, UHillen, MHGFoppen, SMGoldinger, JUtikal, JCHassel, BWeide, KCKaehler, CLoquai, PMohr, R Gutzmer, RDummer, SGabriel, CJWu, D Schadendorf, LAGarraway. Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science 2015; 350(6257): 207–211 pmid: 26359337
61 NMcGranahan, AJ Furness, RRosenthal, SRamskov, RLyngaa, SKSaini, MJamal-Hanjani, GAWilson, NJBirkbak, CTHiley, TBWatkins, SShafi, NMurugaesu, RMitter, AUAkarca, JLinares, TMarafioti, JYHenry, EMVan Allen, DMiao, B Schilling, DSchadendorf, LAGarraway, VMakarov, NARizvi, ASnyder, MDHellmann, TMerghoub, JDWolchok, SAShukla, CJWu, KS Peggs, TAChan, SRHadrup, SAQuezada, CSwanton. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 2016; 351(6280): 1463–1469 pmid: 26940869
62 MDHellmann, TE Ciuleanu, APluzanski, JSLee, GA Otterson, CAudigier-Valette, EMinenza, HLinardou, SBurgers, PSalman, HBorghaei, SSRamalingam, JBrahmer, MReck, KJ O’Byrne, WJGeese, GGreen, HChang, JSzustakowski, PBhagavatheeswaran, DHealey, YFu, F Nathan, LPaz-Ares. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med 2018; 378(22): 2093–2104 pmid: 29658845
63 MDHellmann, MK Callahan, MMAwad, ECalvo, PAAscierto, AAtmaca, NARizvi, FRHirsch, GSelvaggi, JDSzustakowski, ASasson, RGolhar, PVitazka, HChang, WJGeese, SJAntonia. Tumor mutational burden and efficacy of nivolumab monotherapy and in combination with ipilimumab in small-cell lung cancer. Cancer Cell 2018; 33(5): 853–861.e4 pmid: 29731394
64 MReck, D Rodríguez-Abreu, AGRobinson, RHui, T Csőszi, AFülöp, MGottfried, NPeled, ATafreshi, SCuffe, MO’Brien, SRao, K Hotta, MALeiby, GMLubiniecki, YShentu, RRangwala, JRBrahmer; KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 2016; 375(19): 1823–1833 pmid: 27718847
65 RSHerbst, P Baas, DWKim, EFelip, JLPérez-Gracia, JYHan, J Molina, JHKim, CDArvis, MJAhn, M Majem, MJFidler, Gde Castro Jr, MGarrido, GMLubiniecki, YShentu, EIm, M Dolled-Filhart, EBGaron. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 2016; 387(10027): 1540–1550 pmid: 26712084
66 STKim, R Cristescu, AJBass, KMKim, JI Odegaard, KKim, XQLiu, X Sher, HJung, MLee, S Lee, SHPark, JOPark, YSPark, HYLim, H Lee, MChoi, ATalasaz, PSKang, JCheng, ALoboda, JLee, WK Kang. Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer. Nat Med 2018; 24(9): 1449–1458 pmid: 30013197
[1] Ruiting Han, Junli Ma, Houkai Li. Mechanistic and therapeutic advances in non-alcoholic fatty liver disease by targeting the gut microbiota[J]. Front. Med., 2018, 12(6): 645-657.
[2] Liqin Wang, Rene Bernards. Taking advantage of drug resistance, a new approach in the war on cancer[J]. Front. Med., 2018, 12(4): 490-495.
[3] Minhong Shen, Yibin Kang. Complex interplay between tumor microenvironment and cancer therapy[J]. Front. Med., 2018, 12(4): 426-439.
[4] Haican Liu, Yuanyuan Zhang, Zhiguang Liu, Jinghua Liu, Yolande Hauck, Jiao Liu, Haiyan Dong, Jie Liu, Xiuqin Zhao, Bing Lu, Yi Jiang, Gilles Vergnaud, Christine Pourcel, Kanglin Wan. Associations between Mycobacterium tuberculosis Beijing genotype and drug resistance to four first-line drugs: a survey in China[J]. Front. Med., 2018, 12(1): 92-97.
[5] Yufeng Zhao, Bo Liu, Liyun He, Wenjing Bai, Xueyun Yu, Xinyu Cao, Lin Luo, Peijing Rong, Yuxue Zhao, Guozheng Li, Baoyan Liu. A novel classification method for aid decision of traditional Chinese patent medicines for stroke treatment[J]. Front. Med., 2017, 11(3): 432-439.
[6] Yongfei Hu, George F. Gao, Baoli Zhu. The antibiotic resistome: gene flow in environments, animals and human beings[J]. Front. Med., 2017, 11(2): 161-168.
[7] Ying Ma,Nanxue Zhang,Shi Wu,Haihui Huang,Yanpei Cao. Antimicrobial activity of topical agents against Propionibacterium acnes: an in vitro study of clinical isolates from a hospital in Shanghai, China[J]. Front. Med., 2016, 10(4): 517-521.
[8] Lixia Gan,Wei Xiang,Bin Xie,Liqing Yu. Molecular mechanisms of fatty liver in obesity[J]. Front. Med., 2015, 9(3): 275-287.
[9] Juan Zheng,Shih-Lung Woo,Xiang Hu,Rachel Botchlett,Lulu Chen,Yuqing Huo,Chaodong Wu. Metformin and metabolic diseases: a focus on hepatic aspects[J]. Front. Med., 2015, 9(2): 173-186.
[10] Jianping Ye. Beneficial metabolic activities of inflammatory cytokine interleukin 15 in obesity and type 2 diabetes[J]. Front. Med., 2015, 9(2): 139-145.
[11] Peter B. Alexander,Xiao-Fan Wang. Resistance to receptor tyrosine kinase inhibition in cancer: molecular mechanisms and therapeutic strategies[J]. Front. Med., 2015, 9(2): 134-138.
[12] Douglas D. Fang, Joan Cao, Jitesh P. Jani, Konstantinos Tsaparikos, Alessandra Blasina, Jill Kornmann, Maruja E. Lira, Jianying Wang, Zuzana Jirout, Justin Bingham, Zhou Zhu, Yin Gu, Gerrit Los, Zdenek Hostomsky, Todd VanArsdale. Combined gemcitabine and CHK1 inhibitor treatment induces apoptosis resistance in cancer stem cell-like cells enriched with tumor spheroids from a non-small cell lung cancer cell line[J]. Front Med, 2013, 7(4): 462-476.
[13] Yingjiang Zhou, Liangyou Rui. Leptin signaling and leptin resistance[J]. Front Med, 2013, 7(2): 207-222.
[14] Jingyi Lu, Guoxiang Xie, Weiping Jia, Wei Jia. Insulin resistance and the metabolism of branched-chain amino acids[J]. Front Med, 2013, 7(1): 53-59.
[15] Xiao Miao, Weixia Sun, Yaowen Fu, Lining Miao, Lu Cai. Zinc homeostasis in the metabolic syndrome and diabetes[J]. Front Med, 2013, 7(1): 31-52.
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