Please wait a minute...
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) : 32-44    https://doi.org/10.1007/s11684-018-0678-0
REVIEW |
Monitoring checkpoint inhibitors: predictive biomarkers in immunotherapy
Min Zhang, Jingwen Yang, Wenjing Hua, Zhong Li, Zenghui Xu(), Qijun Qian()
ShangHai Cell Therapy Group Co., Ltd., Shanghai 201805, China
 Download: PDF(351 KB)   HTML
 Export: BibTeX | EndNote | Reference Manager | ProCite | RefWorks
Abstract

Immunotherapy has become the fourth cancer therapy after surgery, chemotherapy, and radiotherapy. In particular, immune checkpoint inhibitors are proved to be unprecedentedly in increasing the overall survival rates of patients with refractory cancers, such as advanced melanoma, non-small cell lung cancer, and renal cell carcinoma. However, inhibitor therapies are only effective in a small proportion of patients with problems, such as side effects and high costs. Therefore, doctors urgently need reliable predictive biomarkers for checkpoint inhibitor therapies to choose the optimal therapies. Here, we review the biomarkers that can serve as potential predictors of the outcomes of immune checkpoint inhibitor treatment, including tumor-specific profiles and tumor microenvironment evaluation and other factors.

Keywords immune checkpoint      companion diagnosis      PD-L1      tumor mutation burden      immune score     
Corresponding Authors: Zenghui Xu,Qijun Qian   
Just Accepted Date: 10 January 2019   Online First Date: 25 January 2019    Issue Date: 12 March 2019
 Cite this article:   
Min Zhang,Jingwen Yang,Wenjing Hua, et al. Monitoring checkpoint inhibitors: predictive biomarkers in immunotherapy[J]. Front. Med., 2019, 13(1): 32-44.
 URL:  
http://academic.hep.com.cn/fmd/EN/10.1007/s11684-018-0678-0
http://academic.hep.com.cn/fmd/EN/Y2019/V13/I1/32
Fig.1  Potential biomarkers for checkpoint inhibitors in category. Tumor-specific atlas (left) includes the expression of PD-L1, neoantigen, and MSI. Tumor microenvironment (right) includes tumor-infiltrating lymphocytes and immune score (not shown in the figure). Biomarkers in the serum (below) contains molecules CRP, LDH, and IL-6 and lymphocytes in the epithelial serum.
Target Drug trade name
(generic name)
Device trade name PMA Intended use
PD-L1 KEYTRUDE®
(Pembrolizumab)
PD-L1 IHC 22C3 pharmDx P150013/S011 Companion diagnostic devices
?Non-small cell lung cancer (NSCLC)
??The specimen should be considered to exhibit PD-L1 expression if TPS≥1% ???and high PD-L1 expression if TPS≥50%
?Gastric or gastresophageal junction (GEJ) adenocarcinoma
??The specimen should be considered to exhibit PD-L1 expression if CPS≥1
Cervical cancer
??The specimen should be considered to exhibit PD-L1 expression if CPS≥1
Urothelial carcinoma
??The specimen should be considered to exhibit PD-L1 expression if CPS≥10
P150013/S006 Companion diagnostic devices
?Non-small cell lung cancer (NSCLC)
??The specimen should be considered to exhibit PD-L1 expression if TPS≥1 ???and high PD-L1 expression if TPS≥50%
P150013/S001 Companion diagnostic devices
?Non-small cell lung cancer (NSCLC)
??The specimen should be considered PD-L1 positive if TPS≥50% of the ???viable tumor cells exhibit membrane staining at any intensity
OPDIVO®
(Nivolumab)
PD-L1 28-8 pharmDx P150027/P150027 Complementary diagnostic devices
?Non-small cell lung cancer (NSCLC)
??A minimum of 100 viable tumor cells must be present for the specimen to be ???considered adequate for PD-L1 evaluation
?Melanoma
??Specimen is considered PD-L1 positive if≥1% of melanoma cells exhibit ???circumferential and/or partial linear plasma membrane PD-L1 staining of ???tumor cells at any intensity
TECENTRIQ®
(Atezolizumab)
PD-L1 (SP142) P16002/S006 Companion diagnostic devices
?Urothelial carcinoma
??PD-L1 expression≥5% IC is indicated as an aid in identifying urothelial ???carcinoma patients
?Non-small cell lung cancer (NSCLC)
??PD-L1 expression≥50% TC or≥10% IC may be associated with enhanced ???overall survival
IMFINZI®
(Durvalumab)
PD-L1 SP263 P160046 Complementary diagnostic devices
?Advanced or metastatic urothelial carcinoma
??PD-L1 status is considered high if any of the following are met: (1)≥25% of ???tumor cells exhibit membrane staining; (2) ICP>1% and IC+≥25%;(3) ICP???= 1% and IC+ = 100%
Tab.1  List of diagnostic devices approved by FDA
1 HBorghaei, L Paz-Ares, LHorn, DRSpigel, MSteins, NEReady, LQChow, EEVokes, EFelip, EHolgado, FBarlesi, MKohlhäufl, OArrieta, MABurgio, JFayette, HLena, E Poddubskaya, DEGerber, SNGettinger, CMRudin, NRizvi, LCrinò, GRBlumenschein Jr, SJAntonia, CDorange, CTHarbison, FGraf Finckenstein, JRBrahmer. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 2015; 373(17): 1627–1639
https://doi.org/10.1056/NEJMoa1507643 pmid: 26412456
2 JBrahmer, KL Reckamp, PBaas, LCrinò, WEEberhardt, EPoddubskaya, SAntonia, APluzanski, EEVokes, EHolgado, DWaterhouse, NReady, JGainor, OArén Frontera, LHavel, MSteins, MCGarassino, JGAerts, MDomine, LPaz-Ares, MReck, C Baudelet, CTHarbison, BLestini, DRSpigel. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 2015; 373(2): 123–135
https://doi.org/10.1056/NEJMoa1504627 pmid: 26028407
3 EBGaron, NA Rizvi, RHui, NLeighl, ASBalmanoukian, JPEder, APatnaik, CAggarwal, MGubens, LHorn, E Carcereny, MJAhn, EFelip, JSLee, MD Hellmann, OHamid, JWGoldman, JCSoria, MDolled-Filhart, RZRutledge, JZhang, JKLunceford, RRangwala, GMLubiniecki, CRoach, KEmancipator, L; KEYNOTE-001 Investigators.Gandhi Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 2015; 372(21): 2018–2028
https://doi.org/10.1056/NEJMoa1501824 pmid: 25891174
4 JLarkin, V Chiarion-Sileni, RGonzalez, JJGrob, CLCowey, CDLao, D Schadendorf, RDummer, MSmylie, PRutkowski, PFFerrucci, AHill, J Wagstaff, MSCarlino, JBHaanen, MMaio, I Marquez-Rodas, GAMcArthur, PAAscierto, GVLong, MKCallahan, MAPostow, KGrossmann, MSznol, BDreno, LBastholt, AYang, LM Rollin, CHorak, FSHodi, JDWolchok. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 2015; 373(1): 23–34
https://doi.org/10.1056/NEJMoa1504030 pmid: 26027431
5 CRobert, GV Long, BBrady, CDutriaux, MMaio, L Mortier, JCHassel, PRutkowski, CMcNeil, EKalinka-Warzocha, KJSavage, MMHernberg, CLebbé, JCharles, CMihalcioiu, VChiarion-Sileni, CMauch, FCognetti, AArance, HSchmidt, DSchadendorf, HGogas, LLundgren-Eriksson, CHorak, BSharkey, IMWaxman, VAtkinson, PAAscierto. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 2015; 372(4): 320–330
https://doi.org/10.1056/NEJMoa1412082 pmid: 25399552
6 MReck. Pembrolizumab as first-line therapy for metastatic non-small-cell lung cancer. Immunotherapy 2018; 10(2): 93–105
https://doi.org/10.2217/imt-2017-0121 pmid: 29145737
7 YLWTony Mok, Watson PA, Zhang J, Rangwala RA, Lopes G. Phase 3 KEYNOTE-042 trial of pembrolizumab (MK-3475) versus platinum doublet chemotherapy in treatment-naive patients (pts) with PD-L1–positive advanced non-small cell lung cancer (NSCLC). J Clin Oncol. 2015; 33(15_suppl): TPS8105
8 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
https://doi.org/10.1056/NEJMoa1801946 pmid: 29658845
9 RJMotzer, NM Tannir, DFMcDermott, OArén Frontera, BMelichar, TKChoueiri, ERPlimack, PBarthélémy, CPorta, SGeorge, TPowles, FDonskov, VNeiman, CKKollmannsberger, PSalman, HGurney, RHawkins, ARavaud, MOGrimm, SBracarda, CHBarrios, YTomita, DCastellano, BIRini, ACChen, SMekan, MBMcHenry, MWind-Rotolo, JDoan, P Sharma, HJHammers, BEscudier; CheckMate 214 Investigators. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med 2018; 378(14): 1277–1290
https://doi.org/10.1056/NEJMoa1712126 pmid: 29562145
10 IMárquez-Rodas, PCerezuela, ASoria, ABerrocal, ARiso, M González-Cao, SMartín-Algarra. Immune checkpoint inhibitors: therapeutic advances in melanoma. Ann Transl Med 2015; 3(18): 267
pmid: 26605313
11 RALovell, DJ Schaeffer, SBHooser,  WMHaschek,  AMDahlem,  WWCarmichael,  VRBeasley. Toxicity of intraperitoneal doses of microcystin-LR in two strains of male mice. J Environ Pathol Toxicol Oncol 1989; 9(3): 221–237
12 DSchadendorf, FS Hodi, CRobert, JSWeber, KMargolin, OHamid, DPatt, TT Chen, DMBerman, JDWolchok. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J Clin Oncol 2015; 33(17): 1889–1894
https://doi.org/10.1200/JCO.2014.56.2736 pmid: 25667295
13 JSWeber, SP D’Angelo, DMinor, FSHodi, RGutzmer, BNeyns, CHoeller, NIKhushalani, WHMiller Jr, CDLao, GP Linette, LThomas, PLorigan, KFGrossmann, JCHassel, MMaio, M Sznol, PAAscierto, PMohr, B Chmielowski, ABryce, IMSvane, JJGrob, AMKrackhardt, CHorak, ALambert, ASYang, JLarkin. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol 2015; 16(4): 375–384
https://doi.org/10.1016/S1470-2045(15)70076-8 pmid: 25795410
14 JMTaube, GD Young, TLMcMiller,  TLMcMiller, SM Chen, JTSalas,  TSPritchard,  HY Xu,  AKMeeker,  JHFan,  C Cheadle,  AEBerger,  DMPardoll, SL Topalian. Differential expression of immune-regulatory genes associated with PD-L1 display in melanoma: implications for PD-1 pathway blockade. Clin Cancer Res 2015; 21(17): 3969–3976
15 RSHerbst, JC Soria, MKowanetz, GDFine, OHamid, MSGordon, JASosman, DFMcDermott, JDPowderly, SNGettinger, HEKohrt, LHorn, DP Lawrence, SRost, MLeabman, YXiao, A Mokatrin, HKoeppen, PSHegde, IMellman, DSChen, FSHodi. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 2014; 515(7528): 563–567
https://doi.org/10.1038/nature14011 pmid: 25428504
16 JMTaube, A Klein, JRBrahmer, HYXu , XY Pan, JH Kim, LPChen, DMPardoll, SLTopalian, RA. Anders Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res 2014; 20(19): 5064–5074
17 SLTopalian, FS Hodi, JRBrahmer, SNGettinger, DCSmith, DFMcDermott, JDPowderly, RDCarvajal, JASosman, MBAtkins, PDLeming, DRSpigel, SJAntonia, LHorn, CG Drake, DMPardoll, LChen, WH Sharfman, RAAnders, JMTaube, TLMcMiller, HXu, AJ Korman, MJure-Kunkel, SAgrawal, DMcDonald, GDKollia, AGupta, JMWigginton, MSznol. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012; 366(26): 2443–2454
https://doi.org/10.1056/NEJMoa1200690 pmid: 22658127
18 RJMotzer, B Escudier, DFMcDermott, SGeorge, HJHammers, SSrinivas, SSTykodi, JASosman, GProcopio, ERPlimack, DCastellano, TKChoueiri, HGurney, FDonskov, PBono, J Wagstaff, TCGauler, TUeda, Y Tomita, FASchutz, CKollmannsberger, JLarkin, ARavaud, JSSimon, LAXu, IM Waxman, PSharma; CheckMate 025 Investigators. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015; 373(19): 1803–1813
https://doi.org/10.1056/NEJMoa1510665 pmid: 26406148
19 JSLim, R Sundar, MChénard-Poirier, JLopez, TAYap. Emerging biomarkers for PD-1 pathway cancer therapy. Biomarkers Med 2017; 11(1): 53–67
https://doi.org/10.2217/bmm-2016-0228 pmid: 27936870
20 JMTaube, RA Anders, GDYoung, HXu, R Sharma, TLMcMiller, SChen, AP Klein, DMPardoll, SLTopalian, LChen. Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl Med 2012; 4(127): 127ra37
https://doi.org/10.1126/scitranslmed.3003689 pmid: 22461641
21 ZFeng, S Puri, TMoudgil, WWood, CC Hoyt, CWang, WJUrba, BDCurti, CBBifulco, BAFox. Multispectral imaging of formalin-fixed tissue predicts ability to generate tumor-infiltrating lymphocytes from melanoma. J Immunother Cancer 2015; 3(1): 47
https://doi.org/10.1186/s40425-015-0091-z pmid: 26500776
22 ECStack, PG Foukas, PPLee. Multiplexed tissue biomarker imaging. J Immunother Cancer 2016; 4(1): 9
https://doi.org/10.1186/s40425-016-0115-3 pmid: 26885371
23 SPPatel, R Kurzrock. PD-L1 expression as a predictive biomarker in cancer immunotherapy. Mol Cancer Ther 2015; 14(4): 847–856
https://doi.org/10.1158/1535-7163.MCT-14-0983 pmid: 25695955
24 WYSun, YK Lee, JSKoo. Expression of PD-L1 in triple-negative breast cancer based on different immunohistochemical antibodies. J Transl Med 2016; 14(1): 173
https://doi.org/10.1186/s12967-016-0925-6 pmid: 27286842
25 PCTumeh, CL Harview, JHYearley, IPShintaku, EJTaylor, LRobert, BChmielowski, MSpasic, GHenry, VCiobanu, ANWest, MCarmona, CKivork, ESeja, G Cherry, AJGutierrez, TRGrogan, CMateus, GTomasic, JAGlaspy, ROEmerson, HRobins, RHPierce, DAElashoff, CRobert, ARibas. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 2014; 515(7528): 568–571
https://doi.org/10.1038/nature13954 pmid: 25428505
26 JMarianne. AS Ratcliffe, AMidha, CBarker, PScorer, JWalker. A comparative study of PD-L1 diagnostic assays and the classification of patients as PD-L1 positive and PD-L1 negative. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16–20; New Orleans, LA. Philadelphia (PA): AACR. Cancer Res 2016; 76(14 Suppl): Abstract nr LB-094
27 DTLe, JN Uram, HWang, BRBartlett, HKemberling, ADEyring, ADSkora, BSLuber, NSAzad, DLaheru, BBiedrzycki, RCDonehower, AZaheer, GAFisher, TSCrocenzi, JJLee, SM Duffy, RMGoldberg, Ade la Chapelle, MKoshiji, FBhaijee, THuebner, RHHruban, LDWood, NCuka, DM Pardoll, NPapadopoulos, KWKinzler, SZhou, TC Cornish, JMTaube, RAAnders, JREshleman, BVogelstein, LADiaz Jr. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 2015; 372(26): 2509–2520
https://doi.org/10.1056/NEJMoa1500596 pmid: 26028255
28 NARizvi, MD Hellmann, ASnyder, PKvistborg, VMakarov, JJHavel, WLee, J Yuan, PWong, TSHo, ML Miller, NRekhtman, ALMoreira, FIbrahim, CBruggeman, BGasmi, RZappasodi, YMaeda, CSander, EBGaron, TMerghoub, JDWolchok, TNSchumacher, TAChan. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 2015; 348(6230): 124–128
https://doi.org/10.1126/science.aaa1348 pmid: 25765070
29 MSLawrence, P Stojanov, PPolak, GVKryukov, KCibulskis, ASivachenko, SLCarter, CStewart, CHMermel, SARoberts, AKiezun, PSHammerman, AMcKenna, YDrier, LZou, AH Ramos, TJPugh, NStransky, EHelman, JKim, C Sougnez, LAmbrogio, ENickerson, EShefler, MLCortés, DAuclair, GSaksena, DVoet, M Noble, DDiCara, PLin, L Lichtenstein, DIHeiman, TFennell, MImielinski, BHernandez, EHodis, SBaca, AM Dulak, JLohr, DALandau, CJWu, J Melendez-Zajgla, AHidalgo-Miranda, AKoren, SAMcCarroll, JMora, B Crompton, ROnofrio, MParkin, WWinckler, KArdlie, SBGabriel, CWMRoberts, JABiegel, KStegmaier, AJBass, LAGarraway, MMeyerson, TRGolub, DAGordenin, SSunyaev, ESLander, GGetz. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 2013; 499(7457): 214–218
https://doi.org/10.1038/nature12213 pmid: 23770567
30 ASnyder, V Makarov, TMerghoub, JYuan, JM Zaretsky, ADesrichard, LAWalsh, MAPostow, PWong, TS Ho, TJHollmann, CBruggeman, KKannan, YLi, C Elipenahli, CLiu, CTHarbison, LWang, A Ribas, JDWolchok, TAChan. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med 2014; 371(23): 2189–2199
https://doi.org/10.1056/NEJMoa1406498 pmid: 25409260
31 JERosenberg, J Hoffman-Censits, TPowles, MSvan der Heijden, AVBalar, ANecchi, NDawson, PHO’Donnell, ABalmanoukian, YLoriot, SSrinivas, MMRetz, PGrivas, RWJoseph, MDGalsky, MTFleming, DPPetrylak, JLPerez-Gracia, HABurris, DCastellano, CCanil, JBellmunt, DBajorin, DNickles, RBourgon, GMFrampton, NCui, S Mariathasan, OAbidoye, GDFine, RDreicer. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 2016; 387(10031): 1909–1920
https://doi.org/10.1016/S0140-6736(16)00561-4 pmid: 26952546
32 KRSpencer, J Wang, AWSilk, SGanesan, HLKaufman, JMMehnert. Biomarkers for immunotherapy: current developments and challenges. Am Soc Clin Oncol Educ Book 2016; 35(36): e493–e503
https://doi.org/10.1200/EDBK_160766 pmid: 27249758
33 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
https://doi.org/10.1126/science.aaf1490 pmid: 26940869
34 MEBirnbaum, JL Mendoza, DKSethi, SDong, J Glanville, JDobbins, EOzkan, MMDavis, KWWucherpfennig, KCGarcia. Deconstructing the peptide-MHC specificity of T cell recognition. Cell 2014; 157(5): 1073–1087
https://doi.org/10.1016/j.cell.2014.03.047 pmid: 24855945
35 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
https://doi.org/10.1126/science.aad0095 pmid: 26359337
36 JWDrake, B Charlesworth, DCharlesworth, JFCrow. Rates of spontaneous mutation. Genetics 1998; 148(4): 1667–1686
pmid: 9560386
37 TAKunkel, K Bebenek. DNA replication fidelity. Annu Rev Biochem 2000; 69(1): 497–529
https://doi.org/10.1146/annurev.biochem.69.1.497 pmid: 10966467
38 BDPreston, TM Albertson, AJHerr. DNA replication fidelity and cancer. Semin Cancer Biol 2010; 20(5): 281–293
https://doi.org/10.1016/j.semcancer.2010.10.009 pmid: 20951805
39 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
https://doi.org/10.1126/science.aan6733 pmid: 28596308
40 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 2016; 165(1): 35–44
https://doi.org/10.1016/j.cell.2016.02.065 pmid: 26997480
41 TFGajewski, H Schreiber, YXFu. Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol 2013; 14(10): 1014–1022
https://doi.org/10.1038/ni.2703 pmid: 24048123
42 JGalon, A Costes, FSanchez-Cabo, AKirilovsky, BMlecnik, CLagorce-Pagès, MTosolini, MCamus, ABerger, PWind, F Zinzindohoué, PBruneval, PHCugnenc, ZTrajanoski, WHFridman, FPagès. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 2006; 313(5795): 1960–1964
https://doi.org/10.1126/science.1129139 pmid: 17008531
43 CJochems, J Schlom. Tumor-infiltrating immune cells and prognosis: the potential link between conventional cancer therapy and immunity. Exp Biol Med (Maywood) 2011; 236(5): 567–579
https://doi.org/10.1258/ebm.2011.011007 pmid: 21486861
44 BMlecnik, M Tosolini, AKirilovsky, ABerger, GBindea, TMeatchi, PBruneval, ZTrajanoski, WHFridman, FPagès, JGalon. Histopathologic-based prognostic factors of colorectal cancers are associated with the state of the local immune reaction. J Clin Oncol 2011; 29(6): 610–618
https://doi.org/10.1200/JCO.2010.30.5425 pmid: 21245428
45 FPagès, A Berger, MCamus, FSanchez-Cabo, ACostes, RMolidor, BMlecnik, AKirilovsky, MNilsson, DDamotte, TMeatchi, PBruneval, PHCugnenc, ZTrajanoski, WHFridman, JGalon. Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med 2005; 353(25): 2654–2666
https://doi.org/10.1056/NEJMoa051424 pmid: 16371631
46 HMKluger, CR Zito, MLBarr, HMKluger , CRZito ,  MLBarr , MK Baine ,VLS Chiang , MSznol , DLRimm ,  LPChen ,  LB Jilaveanu . Characterization of PD-L1 expression and associated T-cell infiltrates in metastatic melanoma samples from variable anatomic sites. Clin Cancer Res 2015; 21(13): 3052–3060
47 LZhang, JR Conejo-Garcia, DKatsaros, PAGimotty, MMassobrio, GRegnani, AMakrigiannakis, HGray, K Schlienger, MNLiebman, SCRubin, GCoukos. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med 2003; 348(3): 203–213
https://doi.org/10.1056/NEJMoa020177 pmid: 12529460
48 ALadanyi, B Somlai, KGilde, ZFejos, IGaudi, JTimar. T-cell activation marker expression on tumor-infiltrating lymphocytes as prognostic factor in cutaneous malignant melanoma. Clin Cancer Res 2004; 10(2): 521–530
49 KHiraoka, M Miyamoto, YCho, MSuzuoki, TOshikiri, YNakakubo, TItoh, T Ohbuchi, SKondo, HKatoh. Concurrent infiltration by CD8+ T cells and CD4+ T cells is a favourable prognostic factor in non-small-cell lung carcinoma. Br J Cancer 2006; 94(2): 275–280
https://doi.org/10.1038/sj.bjc.6602934 pmid: 16421594
50 LCalabrò, M Maio. Immune checkpoint blockade in malignant mesothelioma. Semin Oncol 2015; 42(3): 418–422
https://doi.org/10.1053/j.seminoncol.2015.02.001 pmid: 25965359
51 HChen, CI Liakou, AKamat, CPettaway, JFWard, DNTang, JSun, AA Jungbluth, PTroncoso, CLogothetis, PSharma. Anti-CTLA-4 therapy results in higher CD4+ICOShi T cell frequency and IFN-γ levels in both nonmalignant and malignant prostate tissues. Proc Natl Acad Sci USA 2009; 106(8): 2729–2734
https://doi.org/10.1073/pnas.0813175106 pmid: 19202079
52 CILiakou, A Kamat, DNTang, HChen, J Sun, PTroncoso, CLogothetis, PSharma. CTLA-4 blockade increases IFNγ-producing CD4+ICOShi cells to shift the ratio of effector to regulatory T cells in cancer patients. Proc Natl Acad Sci USA 2008; 105(39): 14987–14992
https://doi.org/10.1073/pnas.0806075105 pmid: 18818309
53 RHVonderheide, PM LoRusso, MKhalil,  EMGartner,  DKhaira,  DSoulieres,  PDorazio,  JATrosko,  JRüter,  GLMariani,  TUsari, SMDomchek. Tremelimumab in combination with exemestane in patients with advanced breast cancer and treatment-associated modulation of inducible costimulator expression on patient T cells. Clin Cancer Res 2010; 16(13): 3485–3494
54 DNg Tang, Y Shen, JSun, SWen, JD Wolchok, JYuan, JPAllison, PSharma. Increased frequency of ICOS+ CD4 T cells as a pharmacodynamic biomarker for anti-CTLA-4 therapy. Cancer Immunol Res 2013; 1(4): 229–234
https://doi.org/10.1158/2326-6066.CIR-13-0020 pmid: 24777852
55 JWHuh, JH Lee, HRKim. Prognostic significance of tumor-infiltrating lymphocytes for patients with colorectal cancer. Arch Surg 2012; 147(4): 366–372
https://doi.org/10.1001/archsurg.2012.35 pmid: 22508783
56 NEThomas, KJ Busam, LFrom, AKricker, BKArmstrong, HAnton-Culver, SBGruber, RPGallagher, RZanetti, SRosso, TDwyer, AVenn, PA Kanetsky, PAGroben, HHao, I Orlow, ASReiner, LLuo, S Paine, DWOllila, HWilcox, CBBegg, MBerwick. Tumor-infiltrating lymphocyte grade in primary melanomas is independently associated with melanoma-specific survival in the population-based genes, environment and melanoma study. J Clin Oncol 2013; 31(33): 4252–4259
https://doi.org/10.1200/JCO.2013.51.3002 pmid: 24127443
57 DQZeng, YF Yu, QYOu, XYLi, RZ Zhong, CMXie, QGHu. Prognostic and predictive value of tumor-infiltrating lymphocytes for clinical therapeutic research in patients with non-small cell lung cancer. Oncotarget 2016; 7(12): 13765–13781
https://doi.org/10.18632/oncotarget.7282 pmid: 26871598
58 JLMessina, DA Fenstermacher, SEschrich, XQu, AE Berglund, MCLloyd, MJSchell, VKSondak, JSWeber, JJMulé. 12-Chemokine gene signature identifies lymph node-like structures in melanoma: potential for patient selection for immunotherapy? Sci Rep 2012; 2(1): 765
https://doi.org/10.1038/srep00765 pmid: 23097687
59 TTokito, K Azuma, AKawahara, HIshii, KYamada, NMatsuo, TKinoshita, NMizukami, HOno, M Kage, THoshino. Predictive relevance of PD-L1 expression combined with CD8+ TIL density in stage III non-small cell lung cancer patients receiving concurrent chemoradiotherapy. Eur J Cancer 2016; 55: 7–14
https://doi.org/10.1016/j.ejca.2015.11.020 pmid: 26771872
60 GTGibney, LM Weiner, MBAtkins. Predictive biomarkers for checkpoint inhibitor-based immunotherapy. Lancet Oncol 2016; 17(12): e542–e551
https://doi.org/10.1016/S1470-2045(16)30406-5 pmid: 27924752
61 OHamid, H Schmidt, ANissan, LRidolfi, SAamdal, JHansson, MGuida, DMHyams, HGómez, LBastholt, SDChasalow, DBerman. A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma. J Transl Med 2011; 9(1): 204
https://doi.org/10.1186/1479-5876-9-204 pmid: 22123319
62 JGalon, B Mlecnik, GBindea, HKAngell, ABerger, CLagorce, ALugli, IZlobec, AHartmann, CBifulco, IDNagtegaal, RPalmqvist, GVMasucci, GBotti, FTatangelo, PDelrio, MMaio, L Laghi, FGrizzi, MAsslaber, CD’Arrigo, FVidal-Vanaclocha, EZavadova, LChouchane, PSOhashi, SHafezi-Bakhtiari, BGWouters, MRoehrl, LNguyen, YKawakami, SHazama, KOkuno, SOgino, PGibbs, PWaring, NSato, T Torigoe, KItoh, PSPatel, SNShukla, YWang, S Kopetz, FASinicrope, VScripcariu, PAAscierto, FMMarincola, BAFox, F Pagès. Towards the introduction of the ‘Immunoscore’ in the classification of malignant tumours. J Pathol 2014; 232(2): 199–209
https://doi.org/10.1002/path.4287 pmid: 24122236
63 JTsuchiya, T Maekawa. Cytokinetic studies on hematopoietic cells of the bone marrow. Nihon Ketsueki Gakkai Zasshi 1973; 36(5): 641–660
64 JGalon, BA Fox, CBBifulco, GMasucci, TRau, G Botti, FMMarincola, GCiliberto, FPages, PAAscierto, MCapone. Immunoscore and immunoprofiling in cancer: an update from the melanoma and immunotherapy bridge 2015. J Transl Med 2016; 14(1): 273
https://doi.org/10.1186/s12967-016-1029-z pmid: 27650038
65 FPagès, A Kirilovsky, BMlecnik, MAsslaber, MTosolini, GBindea, CLagorce, PWind, F Marliot, PBruneval, KZatloukal, ZTrajanoski, ABerger, WHFridman, JGalon. In situ cytotoxic and memory T cells predict outcome in patients with early-stage colorectal cancer. J Clin Oncol 2009; 27(35): 5944–5951
https://doi.org/10.1200/JCO.2008.19.6147 pmid: 19858404
66 MNishino, NH Ramaiya, HHatabu, FSHodi. Monitoring immune-checkpoint blockade: response evaluation and biomarker development. Nat Rev Clin Oncol 2017; 14(11): 655–668
https://doi.org/10.1038/nrclinonc.2017.88 pmid: 28653677
67 PAAscierto, M Capone, WJUrba, CBBifulco, GBotti, ALugli, FMMarincola, GCiliberto, JGalon, BAFox. The additional facet of immunoscore: immunoprofiling as a possible predictive tool for cancer treatment. J Transl Med 2013; 11(1): 54
https://doi.org/10.1186/1479-5876-11-54 pmid: 23452415
68 EEPaulsen ,  TK Kilvaer ,  MRKhanehkenari,  SAl-Saad,  SM Hald ,  SAndersen,  ERichardsen,  NNess,  LTBusund ,  RMBremnes ,  TDonnem. Assessing PDL-1 and PD-1 in non-small cell lung cancer: a novel immunoscore approach. Clin Lung Cancer 2017; 18(2): 220–333.e8
https://doi.org/10.1016/j.cllc.2016.09.009
69 JYuan, J Zhou, ZDong, STandon, DKuk, KS Panageas, PWong, XWu, J Naidoo, DBPage, JDWolchok, FSHodi. Pretreatment serum VEGF is associated with clinical response and overall survival in advanced melanoma patients treated with ipilimumab. Cancer Immunol Res 2014; 2(2): 127–132
https://doi.org/10.1158/2326-6066.CIR-13-0163 pmid: 24778276
70 SKelderman, B Heemskerk, Hvan Tinteren, RRvan den Brom, GAHospers, AJvan den Eertwegh, EWKapiteijn, JWde Groot, PSoetekouw, RLJansen, EFiets, AJFurness, ARenn, M Krzystanek, ZSzallasi, PLorigan, MEGore, TNSchumacher, JBHaanen, JMLarkin, CUBlank. Lactate dehydrogenase as a selection criterion for ipilimumab treatment in metastatic melanoma. Cancer Immunol Immunother 2014; 63(5): 449–458
https://doi.org/10.1007/s00262-014-1528-9 pmid: 24609989
71 ESimeone, G Gentilcore, DGiannarelli, AMGrimaldi, CCaracò, MCurvietto, AEsposito, MPaone, MPalla, ECavalcanti, FSandomenico, APetrillo, GBotti, FFulciniti, GPalmieri, PQueirolo, PMarchetti, VFerraresi, GRinaldi, MPPistillo, GCiliberto, NMozzillo, PAAscierto. Immunological and biological changes during ipilimumab treatment and their potential correlation with clinical response and survival in patients with advanced melanoma. Cancer Immunol Immunother 2014; 63(7): 675–683
https://doi.org/10.1007/s00262-014-1545-8 pmid: 24695951
72 DHannani, M Vétizou, DEnot, SRusakiewicz, NChaput, DKlatzmann, MDesbois, NJacquelot, NVimond, SChouaib, CMateus, JPAllison, ARibas, JDWolchok, JYuan, P Wong, MPostow, AMackiewicz, JMackiewicz, DSchadendorff, DJaeger, IZörnig, JHassel, AJKorman, KBahjat, MMaio, L Calabro, MWTeng, MJSmyth, AEggermont, CRobert, GKroemer, LZitvogel. Anticancer immunotherapy by CTLA-4 blockade: obligatory contribution of IL-2 receptors and negative prognostic impact of soluble CD25. Cell Res 2015; 25(2): 208–224
https://doi.org/10.1038/cr.2015.3 pmid: 25582080
73 JDelyon, C Mateus, DLefeuvre, ELanoy, LZitvogel, NChaput, SRoy, AM Eggermont, ERoutier, CRobert. Experience in daily practice with ipilimumab for the treatment of patients with metastatic melanoma: an early increase in lymphocyte and eosinophil counts is associated with improved survival. Ann Oncol 2013; 24(6): 1697–1703
https://doi.org/10.1093/annonc/mdt027 pmid: 23439861
74 AMartens, K Wistuba-Hamprecht, MGeukes Foppen,   JYuan,  MAPostow ,  PWong,  E,Romano   AKhammari,  BDreno,  MCapone,  PA Ascierto ,  AMDi Giacomo ,  MMaio,  B Schilling,  ASucker,  DSchadendorf,  JC Hassel ,  TKEigentler,  PMartus,  JD Wolchok,  CBlank,  GPawelec,  CGarbe,  BWeide. Baseline peripheral blood biomarkers associated with clinical outcome of advanced melanoma patients treated with ipilimumab. Clin Cancer Res 2016; 22(12): 2908–2918
https://doi.org/10.1158/1078-0432.CCR-15-2412
75 HSchmidt, S Suciu, CJPunt, MGore, W Kruit, PPatel, DLienard, Hvon der Maase, AMEggermont, UKeilholz; American Joint Committee on Cancer Stage IV Melanoma; EORTC 18951. Pretreatment levels of peripheral neutrophils and leukocytes as independent predictors of overall survival in patients with American Joint Committee on Cancer Stage IV Melanoma: results of the EORTC 18951 Biochemotherapy Trial. J Clin Oncol 2007; 25(12): 1562–1569
https://doi.org/10.1200/JCO.2006.09.0274 pmid: 17443000
76 CMeyer, L Cagnon, CMCosta-Nunes, PBaumgaertner, NMontandon, LLeyvraz, OMichielin, ERomano, DESpeiser. Frequencies of circulating MDSC correlate with clinical outcome of melanoma patients treated with ipilimumab. Cancer Immunol Immunother 2014; 63(3): 247–257
https://doi.org/10.1007/s00262-013-1508-5 pmid: 24357148
77 JYuan, M Adamow, BAGinsberg, TSRasalan, ERitter, HFGallardo, YXu, E Pogoriler, SLTerzulli, DKuk, KS Panageas, GRitter, MSznol, RHalaban, AAJungbluth, JPAllison, LJOld, JD Wolchok, SGnjatic. Integrated NY-ESO-1 antibody and CD8+ T-cell responses correlate with clinical benefit in advanced melanoma patients treated with ipilimumab. Proc Natl Acad Sci USA 2011; 108(40): 16723–16728
https://doi.org/10.1073/pnas.1110814108 pmid: 21933959
78 RMandal, TA Chan. Personalized oncology meets immunology: the path toward precision immunotherapy. Cancer Discov 2016; 6(7): 703–713
https://doi.org/10.1158/2159-8290.CD-16-0146 pmid: 27107038
79 ASivan, L Corrales, NHubert, JBWilliams, KAquino-Michaels, ZMEarley, FWBenyamin, YMLei, B Jabri, MLAlegre, EBChang, TFGajewski. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 2015; 350(6264): 1084–1089
https://doi.org/10.1126/science.aac4255 pmid: 26541606
80 MVétizou, JM Pitt, RDaillère, PLepage, NWaldschmitt, CFlament, SRusakiewicz, BRouty, MPRoberti, CPDuong, VPoirier-Colame, ARoux, S Becharef, SFormenti, EGolden, SCording, GEberl, ASchlitzer, FGinhoux, SMani, T Yamazaki, NJacquelot, DPEnot, MBérard, JNigou, POpolon, AEggermont, PLWoerther, EChachaty, NChaput, CRobert, CMateus, GKroemer, DRaoult, IGBoneca, FCarbonnel, MChamaillard, LZitvogel. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 2015; 350(6264): 1079–1084
https://doi.org/10.1126/science.aad1329 pmid: 26541610
81 BRouty, E Le Chatelier, LDerosa, CPMDuong, MTAlou, RDaillère, AFluckiger, MMessaoudene, CRauber, MPRoberti, MFidelle, CFlament, VPoirier-Colame, POpolon, CKlein, KIribarren, LMondragón, NJacquelot, BQu, G Ferrere, CClémenson, LMezquita, JRMasip, CNaltet, SBrosseau, CKaderbhai, CRichard, HRizvi, FLevenez, NGalleron, BQuinquis, NPons, B Ryffel, VMinard-Colin, PGonin, JCSoria, EDeutsch, YLoriot, FGhiringhelli, GZalcman, FGoldwasser, BEscudier, MDHellmann, AEggermont, DRaoult, LAlbiges, GKroemer, LZitvogel. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 2018; 359(6371): 91–97
https://doi.org/10.1126/science.aan3706 pmid: 29097494
82 VGopalakrishnan, CN Spencer, LNezi, AReuben, MCAndrews, TVKarpinets, PAPrieto, DVicente, KHoffman, SCWei, AP Cogdill, LZhao, CWHudgens, DSHutchinson, TManzo, MPetaccia de Macedo, TCotechini, TKumar, WSChen, SMReddy, RSzczepaniak Sloane, JGalloway-Pena, HJiang, PLChen, EJShpall, KRezvani, AMAlousi, RFChemaly, SShelburne, LMVence, PCOkhuysen, VBJensen, AGSwennes, FMcAllister, EMarcelo Riquelme Sanchez, YZhang, ELe Chatelier, LZitvogel, NPons, JL Austin-Breneman, LEHaydu, EMBurton, JMGardner, ESirmans, JHu, AJ Lazar, TTsujikawa, ADiab, H Tawbi, ICGlitza, WJHwu, SP Patel, SEWoodman, RNAmaria, MADavies, JEGershenwald, PHwu, JE Lee, JZhang, LMCoussens, ZACooper, PAFutreal, CRDaniel, NJAjami, JFPetrosino, MTTetzlaff, PSharma, JPAllison, RRJenq, JAWargo. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 2018; 359(6371): 97–103
https://doi.org/10.1126/science.aan4236 pmid: 29097493
83 VMatson, J Fessler, RBao, TChongsuwat, YZha, ML Alegre, JJLuke, TFGajewski. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 2018; 359(6371): 104–108
https://doi.org/10.1126/science.aao3290 pmid: 29302014
[1] 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.
[2] Chenfei Zhou, Jun Zhang. Immunotherapy-based combination strategies for treatment of gastrointestinal cancers: current status and future prospects[J]. Front. Med., 2019, 13(1): 12-23.
[3] Chia-Wei Li, Yun-Ju Lai, Jennifer L. Hsu, Mien-Chie Hung. Activation of phagocytosis by immune checkpoint blockade[J]. Front. Med., 2018, 12(4): 473-480.
[4] Fang Fang, Weihua Xiao, Zhigang Tian. Challenges of NK cell-based immunotherapy in the new era[J]. Front. Med., 2018, 12(4): 440-450.
[5] Yingyan Yu. Molecular classification and precision therapy of cancer: immune checkpoint inhibitors[J]. Front. Med., 2018, 12(2): 229-235.
Viewed
Full text


Abstract

Cited

  Shared   
  Discussed