CoChat
Sign Up
Cited by 165Cancer Immunotherapy and BiomarkersImmunotherapy and Immune ResponsesCancer Genomics and Diagnostics

Genomics of response to immune checkpoint therapies for cancer: implications for precision medicine

Open access
Conway, Jake R., Kofman, Eric, Mo, Shirley S., Elmarakeby, Haitham, Van Allen, Eliezer·2018·Genome Medicine
DOI 10.1186/s13073-018-0605-7PMC PMC6264032
Open this paper in CoChat — free accountOpen PDF

Abstract

Immune checkpoint blockade (ICB) therapies, which potentiate the body’s natural immune response against tumor cells, have shown immense promise in the treatment of various cancers. Currently, tumor mutational burden (TMB) and programmed death ligand 1 (PD-L1) expression are the primary biomarkers evaluated for clinical management of cancer patients across histologies. However, the wide range of responses has demonstrated that the specific molecular and genetic characteristics of each patient’s tumor and immune system must be considered to maximize treatment efficacy. Here, we review the various biological pathways and emerging biomarkers implicated in response to PD-(L)1 and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) therapies, including oncogenic signaling pathways, human leukocyte antigen (HLA) variability, mutation and neoantigen burden, microbiome composition, endogenous retroviruses (ERV), and deficiencies in chromatin remodeling and DNA damage repair (DDR) machinery. We also discuss several mechanisms that have been observed to confer resistance to ICB, such as loss of phosphatase and tensin homolog (PTEN), loss of major histocompatibility complex (MHC) I/II expression, and activation of the indoleamine 2,3-dioxygenase 1 (IDO1) and transforming growth factor beta (TGFβ) pathways. Clinical trials testing the combination of PD-(L)1 or CTLA-4 blockade with molecular mediators of these pathways are becoming more common and may hold promise for improving treatment efficacy and response. Ultimately, some of the genes and molecular mechanisms highlighted in this review may serve as novel biological targets or therapeutic vulnerabilities to improve clinical outcomes in patients.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1186/s13073-018-0605-7

Cites

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • HLA has been identified as a biomarker for predicting ICI response, with higher expression observed in responders.

    “HLA has been identified as a biomarker for predicting ICI response, with higher expression observed in responders (51–53).”

    From PathTIGR: A pathway topology-informed graph representation learning framework for immunotherapy response prediction (2026) · cites this paper as [51]

    The HLA variability section reports that MHC-II expression correlated with better outcomes after PD-1 blockade in Hodgkin lymphoma, while MHC-I and MHC-II expression correlated with efficacy under different treatments in melanoma. It does not establish that HLA expression generally is higher in ICI responders; it also notes that 92% of complete responders in the Hodgkin lymphoma cohort lacked MHC-I expression. The paper treats HLA genetic variability and MHC expression as related but distinct predictors. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • HLA variation and expression levels are important determinants of ICI response.

    “Multiple reviews and original research studies have indicated that HLA variation and expression levels are important determinants of ICI response.”

    From PathTIGR: A pathway topology-informed graph representation learning framework for immunotherapy response prediction (2026) · cites this paper as [51]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

The citation lists haven’t been fetched yet

References 154 · Cited by 165

Research works printed but not linked: 114

  1. [1]Tivol EA Borriello F Schweitzer AN Lynch WP Bluestone JA Sharpe AH Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4 Immunity 1995 3 5 541 547 10.1016/1074-7613(95)90125-6 7584144 · DOI · Paper page
  2. [2]Fife BT Pauken KE Eagar TN Obu T Wu J Tang Q Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR-induced stop signal Nat Immunol 2009 10 11 1185 1192 10.1038/ni.1790 19783989 PMC2778301 · DOI
  3. [5]Quezada SA Peggs KS Exploiting CTLA-4, PD-1 and PD-L1 to reactivate the host immune response against cancer Br J Cancer 2013 108 8 1560 1565 10.1038/bjc.2013.117 23511566 PMC3668483 · DOI
  4. [6]Brunner MC Chambers CA Chan FK Hanke J Winoto A Allison JP CTLA-4-mediated inhibition of early events of T cell proliferation J Immunol 1999 162 10 5813 5820 10229815
  5. [8]Liu Y Cheng Y Xu Y Wang Z Du X Li C Increased expression of programmed cell death protein 1 on NK cells inhibits NK-cell-mediated anti-tumor function and indicates poor prognosis in digestive cancers Oncogene 2017 36 44 6143 6153 10.1038/onc.2017.209 28692048 PMC5671935 · DOI
  6. [9]Freeman GJ Long AJ Iwai Y Bourque K Chernova T Nishimura H 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 10.1084/jem.192.7.1027 11015443 PMC2193311 · DOI · Paper page
  7. [10]Brown JA Dorfman DM Ma F-R Sullivan EL Munoz O Wood CR Blockade of programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine production J Immunol 2003 170 3 1257 1266 10.4049/jimmunol.170.3.1257 12538684 · DOI · Paper page
  8. [11]Iwai Y Ishida M Tanaka Y Okazaki T Honjo T Minato N Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade Proc Natl Acad Sci U S A 2002 99 19 12293 12297 10.1073/pnas.192461099 12218188 PMC129438 · DOI
  9. [12]Topalian SL Drake CG Pardoll DM Targeting the PD-1/B7-H1 (PD-L1) pathway to activate anti-tumor immunity Curr Opin Immunol 2012 2 207 212 10.1016/j.coi.2011.12.009 PMC3319479 22236695 · DOI
  10. [13]Hodi FS O’Day SJ McDermott DF Weber RW Sosman JA Haanen JB Improved survival with ipilimumab in patients with metastatic melanoma N Engl J Med 2010 363 8 711 723 10.1056/NEJMoa1003466 20525992 PMC3549297 · DOI · Paper page
  11. [14]Sharma P Allison JP The future of immune checkpoint therapy Science 2015 348 6230 56 61 10.1126/science.aaa8172 25838373 · DOI · Paper page
  12. [15]Massard C Gordon MS Sharma S Rafii S Wainberg ZA Luke J Safety and efficacy of durvalumab (MEDI4736), an anti-programmed cell death ligand-1 immune checkpoint inhibitor, in patients with advanced urothelial bladder cancer J Clin Oncol 2016 34 26 3119 3125 10.1200/JCO.2016.67.9761 27269937 PMC5569690 · DOI · Paper page
  13. [16]Powles T Durán I van der Heijden MS Loriot Y Vogelzang NJ De Giorgi U Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial Lancet 2018 391 10122 748 757 10.1016/S0140-6736(17)33297-X 29268948 · DOI · Paper page
  14. [19]Topalian SL Hodi FS Brahmer JR Gettinger SN Smith DC McDermott DF Safety, activity, and immune correlates of anti-PD-1 antibody in cancer N Engl J Med 2012 366 26 2443 2454 10.1056/NEJMoa1200690 22658127 PMC3544539 · DOI · Paper page
  15. [20]Tarhini A Immune-mediated adverse events associated with ipilimumab CTLA-4 blockade therapy: the underlying mechanisms and clinical management Scientifica (Cairo) 2013 2013 857519 24278787 PMC3820355
  16. [22]Taube JM Klein A Brahmer JR Xu H Pan X Kim JH 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 10.1158/1078-0432.CCR-13-3271 24714771 PMC4185001 · DOI · Paper page
  17. [23]Gandini S Massi D Mandalà M PD-L1 expression in cancer patients receiving anti PD-1/PD-L1 antibodies: a systematic review and meta-analysis Crit Rev Oncol Hematol 2016 100 88 98 10.1016/j.critrevonc.2016.02.001 26895815 · DOI
  18. [24]Kluger HM Zito CR Turcu G Baine MK Zhang H Adeniran A PD-L1 studies across tumor types, its differential expression and predictive value in patients treated with immune checkpoint inhibitors Clin Cancer Res 2017 23 15 4270 4279 10.1158/1078-0432.CCR-16-3146 28223273 PMC5540774 · DOI
  19. [26]Konishi J Yamazaki K Azuma M Kinoshita I Dosaka-Akita H Nishimura M B7-H1 expression on non-small cell lung cancer cells and its relationship with tumor-infiltrating lymphocytes and their PD-1 expression Clin Cancer Res 2004 10 15 5094 5100 10.1158/1078-0432.CCR-04-0428 15297412 · DOI
  20. [27]Madore J Vilain RE Menzies AM Kakavand H Wilmott JS Hyman J PD-L1 expression in melanoma shows marked heterogeneity within and between patients: implications for anti-PD-1/PD-L 1 clinical trials Pigment Cell Melanoma Res 2015 28 3 245 253 10.1111/pcmr.12340 25477049 · DOI
  21. [28]Dunn GP Bruce AT Ikeda H Old LJ Schreiber RD Cancer immunoediting: from immunosurveillance to tumor escape Nat Immunol 2002 3 11 991 998 10.1038/ni1102-991 12407406 · DOI · Paper page
  22. [29]Rizvi H Sanchez-Vega F La K Chatila W Jonsson P Halpenny D Molecular determinants of response to anti-programmed cell death (PD)-1 and anti-programmed death-ligand 1 (PD-L1) blockade in patients with non-small-cell lung cancer profiled with targeted next-generation sequencing J Clin Oncol 2018 36 7 633 641 10.1200/JCO.2017.75.3384 29337640 PMC6075848 · DOI · Paper page
  23. [31]Snyder A Makarov V Merghoub T Yuan J Zaretsky JM Desrichard A Genetic basis for clinical response to CTLA-4 blockade in melanoma N Engl J Med 2014 371 23 2189 2199 10.1056/NEJMoa1406498 25409260 PMC4315319 · DOI · Paper page
  24. [34]Ansell SM Lesokhin AM Borrello I Halwani A Scott EC Gutierrez M PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma N Engl J Med 2015 372 4 311 319 10.1056/NEJMoa1411087 25482239 PMC4348009 · DOI
  25. [35]Nghiem PT Bhatia S Lipson EJ Kudchadkar RR Miller NJ Annamalai L PD-1 blockade with pembrolizumab in advanced merkel-cell carcinoma N Engl J Med 2016 374 26 2542 2552 10.1056/NEJMoa1603702 27093365 PMC4927341 · DOI · Paper page
  26. [36]Miao D Margolis CA Vokes NI Liu D Taylor-Weiner A Wankowicz SM Genomic correlates of response to immune checkpoint blockade in microsatellite-stable solid tumors Nat Genet 2018 50 9 1271 1281 10.1038/s41588-018-0200-2 30150660 PMC6119118 · DOI · Paper page
  27. [37]Riaz N Morris L Havel JJ Makarov V Desrichard A Chan TA The role of neoantigens in response to immune checkpoint blockade Int Immunol 2016 28 8 411 419 10.1093/intimm/dxw019 27048318 PMC4986233 · DOI
  28. [38]Ott PA Hu Z Keskin DB Shukla SA Sun J Bozym DJ An immunogenic personal neoantigen vaccine for patients with melanoma Nature 2017 547 7662 217 221 10.1038/nature22991 28678778 PMC5577644 · DOI · Paper page
  29. [39]Carreno BM Magrini V Becker-Hapak M Kaabinejadian S Hundal J Petti AA Cancer immunotherapy. A dendritic cell vaccine increases the breadth and diversity of melanoma neoantigen-specific T cells Science 2015 348 6236 803 808 10.1126/science.aaa3828 25837513 PMC4549796 · DOI · Paper page
  30. [40]Kim H Jen J Vogelstein B Hamilton SR Clinical and pathological characteristics of sporadic colorectal carcinomas with DNA replication errors in microsatellite sequences Am J Pathol 1994 145 1 148 156 8030745 PMC1887287
  31. [42]Dolcetti R Viel A Doglioni C Russo A Guidoboni M Capozzi E High prevalence of activated intraepithelial cytotoxic T lymphocytes and increased neoplastic cell apoptosis in colorectal carcinomas with microsatellite instability Am J Pathol 1999 154 6 1805 1813 10.1016/S0002-9440(10)65436-3 10362805 PMC1866613 · DOI
  32. [43]Smyrk TC Watson P Kaul K Lynch HT Tumor-infiltrating lymphocytes are a marker for microsatellite instability in colorectal carcinoma Cancer 2001 91 12 2417 2422 10.1002/1097-0142(20010615)91:12<2417::AID-CNCR1276>3.0.CO;2-U 11413533 · DOI
  33. [44]Strickland KC Howitt BE Shukla SA Rodig S Ritterhouse LL Liu JF Association and prognostic significance of BRCA1/2-mutation status with neoantigen load, number of tumor-infiltrating lymphocytes and expression of PD-1/PD-L1 in high grade serous ovarian cancer Oncotarget 2016 7 12 13587 13598 10.18632/oncotarget.7277 26871470 PMC4924663 · DOI
  34. [45]Teo MY Seier K Ostrovnaya I Regazzi AM Kania BE Moran MM Alterations in DNA damage response and repair genes as potential marker of clinical benefit from PD-1/PD-l1 blockade in advanced urothelial cancers J Clin Oncol 2018 36 17 1685 1694 10.1200/JCO.2017.75.7740 29489427 PMC6366295 · DOI · Paper page
  35. [46]Le DT Durham JN Smith KN Wang H Bartlett BR Aulakh LK Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade Science 2017 357 6349 409 413 10.1126/science.aan6733 28596308 PMC5576142 · DOI · Paper page
  36. [47]Alexandrov LB Nik-Zainal S Wedge DC Aparicio SAJR Behjati S Biankin AV Signatures of mutational processes in human cancer Nature 2013 500 7463 415 421 10.1038/nature12477 23945592 PMC3776390 · DOI · Paper page
  37. [48]Kim ST Cristescu R Bass AJ Kim K-M Odegaard JI Kim K Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer Nat Med 2018 24 9 1449 1458 10.1038/s41591-018-0101-z 30013197 · DOI
  38. [49]McGranahan N Furness AJS Rosenthal R Ramskov S Lyngaa R Saini SK Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade Science 2016 351 6280 1463 1469 10.1126/science.aaf1490 26940869 PMC4984254 · DOI · Paper page
  39. [51]Dhillon AS Hagan S Rath O Kolch W MAP kinase signalling pathways in cancer Oncogene 2007 26 22 3279 3290 10.1038/sj.onc.1210421 17496922 · DOI · Paper page
  40. [52]Loi S Dushyanthen S Beavis PA Salgado R Denkert C Savas P RAS/MAPK activation is associated with reduced tumor-infiltrating lymphocytes in triple-negative breast cancer: therapeutic cooperation between MEK and PD-1/PD-L1 immune checkpoint inhibitors Clin Cancer Res 2016 22 6 1499 1509 10.1158/1078-0432.CCR-15-1125 26515496 PMC4794351 · DOI · Paper page
  41. [53]Hu-Lieskovan S Mok S Homet Moreno B Tsoi J Robert L Goedert L Improved antitumor activity of immunotherapy with BRAF and MEK inhibitors in BRAF(V600E) melanoma Sci Transl Med 2015 7 279 279ra41 10.1126/scitranslmed.aaa4691 25787767 PMC4765379 · DOI
  42. [54]Liu L Mayes PA Eastman S Shi H Yadavilli S Zhang T The BRAF and MEK inhibitors dabrafenib and trametinib: effects on immune function and in combination with immunomodulatory antibodies targeting PD-1, PD-L1, and CTLA-4 Clin Cancer Res 2015 21 7 1639 1651 10.1158/1078-0432.CCR-14-2339 25589619 · DOI · Paper page
  43. [55]D’Souza WN Chang C-F Fischer AM Li M Hedrick SM The Erk2 MAPK regulates CD8 T cell proliferation and survival J Immunol 2008 181 11 7617 7629 10.4049/jimmunol.181.11.7617 19017950 PMC2847891 · DOI
  44. [58]Skoulidis F Byers LA Diao L Papadimitrakopoulou VA Tong P Izzo J Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities Cancer Discov. 2015 5 8 860 877 10.1158/2159-8290.CD-14-1236 26069186 PMC4527963 · DOI · Paper page
  45. [60]Maehama T Dixon JE The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate J Biol Chem 1998 273 22 13375 13378 10.1074/jbc.273.22.13375 9593664 · DOI · Paper page
  46. [61]Liu P Cheng H Roberts TM Zhao JJ Targeting the phosphoinositide 3-kinase pathway in cancer Nat Rev Drug Discov 2009 8 627 644 10.1038/nrd2926 19644473 PMC3142564 · DOI
  47. [62]Keniry M Parsons R The role of PTEN signaling perturbations in cancer and in targeted therapy Oncogene 2008 27 41 5477 5485 10.1038/onc.2008.248 18794882 · DOI
  48. [64]Peng W Chen JQ Liu C Malu S Creasy C Tetzlaff MT Loss of PTEN promotes resistance to T cell-mediated immunotherapy Cancer Discov. 2016 6 2 202 216 10.1158/2159-8290.CD-15-0283 26645196 PMC4744499 · DOI · Paper page
  49. [65]George S Miao D Demetri GD Adeegbe D Rodig SJ Shukla S Loss of PTEN is associated with resistance to anti-PD-1 checkpoint blockade therapy in metastatic uterine leiomyosarcoma Immunity 2017 46 2 197 204 10.1016/j.immuni.2017.02.001 28228279 PMC5408320 · DOI
  50. [66]Millis SZ Ikeda S Reddy S Gatalica Z Kurzrock R Landscape of phosphatidylinositol-3-kinase pathway alterations across 19 784 diverse solid tumors JAMA Oncol. 2016 2 12 1565 1573 10.1001/jamaoncol.2016.0891 27388585 · DOI
  51. [67]Kahn M Can we safely target the WNT pathway? Nat Rev Drug Discov 2014 13 7 513 532 10.1038/nrd4233 24981364 PMC4426976 · DOI
  52. [68]Anastas JN Moon RT WNT signalling pathways as therapeutic targets in cancer Nat Rev Cancer 2013 13 1 11 26 10.1038/nrc3419 23258168 · DOI
  53. [70]Pai SG Carneiro BA Mota JM Costa R Leite CA Barroso-Sousa R Wnt/beta-catenin pathway: modulating anticancer immune response J Hematol Oncol 2017 10 1 101 10.1186/s13045-017-0471-6 28476164 PMC5420131 · DOI
  54. [71]Spranger S Bao R Gajewski TF Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity Nature 2015 523 7559 231 235 10.1038/nature14404 25970248 · DOI · Paper page
  55. [73]Munn DH Mellor AL IDO in the tumor microenvironment: inflammation, counter-regulation, and tolerance Trends Immunol 2016 37 3 193 207 10.1016/j.it.2016.01.002 26839260 PMC4916957 · DOI
  56. [74]Li F Zhang R Li S Liu J IDO1: an important immunotherapy target in cancer treatment Int Immunopharmacol 2017 47 70 77 10.1016/j.intimp.2017.03.024 28365507 · DOI
  57. [75]Toulmonde M Penel N Adam J Chevreau C Blay J-Y Le Cesne A Use of PD-1 targeting, macrophage infiltration, and IDO pathway activation in sarcomas: a phase 2 clinical trial JAMA Oncol. 2018 4 1 93 97 10.1001/jamaoncol.2017.1617 28662235 PMC5833654 · DOI
  58. [76]Zaretsky JM Garcia-Diaz A Shin DS Escuin-Ordinas H Hugo W Hu-Lieskovan S Mutations associated with acquired resistance to PD-1 blockade in melanoma N Engl J Med 2016 375 9 819 829 10.1056/NEJMoa1604958 27433843 PMC5007206 · DOI · Paper page
  59. [78]McGranahan N Rosenthal R Hiley CT Rowan AJ Watkins TBK Wilson GA Allele-specific HLA loss and immune escape in lung cancer evolution Cell 2017 171 6 1259 1271 10.1016/j.cell.2017.10.001 29107330 PMC5720478 · DOI · Paper page
  60. [79]Chowell D Morris LGT Grigg CM Weber JK Samstein RM Makarov V Patient HLA class I genotype influences cancer response to checkpoint blockade immunotherapy Science 2018 359 6375 582 587 10.1126/science.aao4572 29217585 PMC6057471 · DOI · Paper page
  61. [80]Johnson DB Estrada MV Salgado R Sanchez V Doxie DB Opalenik SR Melanoma-specific MHC-II expression represents a tumour-autonomous phenotype and predicts response to anti-PD-1/PD-L1 therapy Nat Commun 2016 7 10582 10.1038/ncomms10582 26822383 PMC4740184 · DOI
  62. [81]Roemer MGM Redd RA Cader FZ Pak CJ Abdelrahman S Ouyang J Major histocompatibility complex class ii and programmed death ligand 1 expression predict outcome after programmed death 1 blockade in classic Hodgkin lymphoma J Clin Oncol 2018 36 10 942 950 10.1200/JCO.2017.77.3994 29394125 PMC5877802 · DOI
  63. [82]Rodig Scott J. Gusenleitner Daniel Jackson Donald G. Gjini Evisa Giobbie-Hurder Anita Jin Chelsea Chang Han Lovitch Scott B. Horak Christine Weber Jeffrey S. Weirather Jason L. Wolchok Jedd D. Postow Michael A. Pavlick Anna C. Chesney Jason Hodi F. Stephen MHC proteins confer differential sensitivity to CTLA-4 and PD-1 blockade in untreated metastatic melanoma Science Translational Medicine 2018 10 450 eaar3342 10.1126/scitranslmed.aar3342 30021886 · DOI · Paper page
  64. [84]Boehm U Klamp T Groot M Howard JC Cellular responses to interferon-γ Annu Rev Immunol 1997 15 1 749 795 10.1146/annurev.immunol.15.1.749 9143706 · DOI · Paper page
  65. [85]Moon JW Kong S-K Kim BS Kim HJ Lim H Noh K IFNγ induces PD-L1 overexpression by JAK2/STAT1/IRF-1 signaling in EBV-positive gastric carcinoma Sci Rep 2017 7 1 17810 10.1038/s41598-017-18132-0 29259270 PMC5736657 · DOI · Paper page
  66. [86]Mimura K Teh JL Okayama H Shiraishi K Kua L-F Koh V PD-L1 expression is mainly regulated by interferon gamma associated with JAK-STAT pathway in gastric cancer Cancer Sci 2018 109 1 43 53 10.1111/cas.13424 29034543 PMC5765310 · DOI
  67. [87]Abiko K Matsumura N Hamanishi J Horikawa N Murakami R Yamaguchi K IFN-γ from lymphocytes induces PD-L1 expression and promotes progression of ovarian cancer Br J Cancer 2015 112 9 1501 1509 10.1038/bjc.2015.101 25867264 PMC4453666 · DOI · Paper page
  68. [88]Goodman AM Piccioni D Kato S Boichard A Wang H-Y Frampton G Prevalence of PDL1 amplification and preliminary response to immune checkpoint blockade in solid tumors JAMA Oncol. 2018 4 9 1237 1244 10.1001/jamaoncol.2018.1701 29902298 PMC6139049 · DOI
  69. [90]Shin DS Zaretsky JM Escuin-Ordinas H Garcia-Diaz A Hu-Lieskovan S Kalbasi A Primary resistance to PD-1 blockade mediated by JAK1/2 mutations Cancer Discov 2017 7 2 188 201 10.1158/2159-8290.CD-16-1223 27903500 PMC5296316 · DOI · Paper page
  70. [92]Van Allen EM Golay HG Liu Y Koyama S Wong K Taylor-Weiner A Long-term benefit of PD-L1 blockade in lung cancer associated with JAK3 activation Cancer Immunol Res 2015 3 8 855 863 10.1158/2326-6066.CIR-15-0024 26014096 PMC4527885 · DOI
  71. [93]Patel SJ Sanjana NE Kishton RJ Eidizadeh A Vodnala SK Cam M Identification of essential genes for cancer immunotherapy Nature 2017 548 7669 537 542 10.1038/nature23477 28783722 PMC5870757 · DOI · Paper page
  72. [94]Luo N Formisano L Gonzalez-Ericsson PI Sanchez V Dean PT Opalenik SR Melanoma response to anti-PD-L1 immunotherapy requires JAK1 signaling, but not JAK2 Oncoimmunology. 2018 7 6 e1438106 10.1080/2162402X.2018.1438106 29872580 PMC5975601 · DOI
  73. [95]Najafi M, Farhood B, Mortezaee K. Contribution of regulatory T cells to cancer: a review. J Cell Physiol. 2018. 10.1002/jcp.27553. 30317612 · DOI
  74. [97]Mariathasan S Turley SJ Nickles D Castiglioni A Yuen K Wang Y TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells Nature 2018 554 7693 544 548 10.1038/nature25501 29443960 PMC6028240 · DOI · Paper page
  75. [98]Shain AH Pollack JR The spectrum of SWI/SNF mutations, ubiquitous in human cancers PLoS One 2013 8 1 e55119 10.1371/journal.pone.0055119 23355908 PMC3552954 · DOI
  76. [99]Kadoch C Hargreaves DC Hodges C Elias L Ho L Ranish J Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy Nat Genet 2013 45 6 592 601 10.1038/ng.2628 23644491 PMC3667980 · DOI
  77. [100]Wang X Haswell JR Roberts CWM Molecular pathways: SWI/SNF (BAF) complexes are frequently mutated in cancer--mechanisms and potential therapeutic insights Clin Cancer Res 2014 20 1 21 27 10.1158/1078-0432.CCR-13-0280 24122795 PMC3947303 · DOI
  78. [103]Zingg D Arenas-Ramirez N Sahin D Rosalia RA Antunes AT Haeusel J The histone methyltransferase Ezh2 controls mechanisms of adaptive resistance to tumor immunotherapy Cell Rep 2017 20 4 854 867 10.1016/j.celrep.2017.07.007 28746871 · DOI
  79. [104]Shu X-S Zhao Y Sun Y Zhong L Cheng Y Zhang Y The epigenetic modifier PBRM1 restricts the basal activity of the innate immune system by repressing retinoic acid-inducible gene-I-like receptor signalling and is a potential prognostic biomarker for colon cancer J Pathol 2018 244 1 36 48 10.1002/path.4986 28940253 · DOI
  80. [105]Abou El Hassan M Huang K MBK E Zhao M Song L Yu T Cancer cells hijack PRC2 to modify multiple cytokine pathways PLoS One 2015 10 6 e0126466 10.1371/journal.pone.0126466 26030458 PMC4450877 · DOI
  81. [106]Jelinic P Ricca J Van Oudenhove E Olvera N Merghoub T Levine DA Immune-active microenvironment in small cell carcinoma of the ovary, hypercalcemic type: rationale for immune checkpoint blockade J Natl Cancer Inst 2018 110 7 787 790 10.1093/jnci/djx277 29365144 PMC6037122 · DOI
  82. [107]Shen J Ju Z Zhao W Wang L Peng Y Ge Z ARID1A deficiency promotes mutability and potentiates therapeutic antitumor immunity unleashed by immune checkpoint blockade Nat Med 2018 24 5 556 562 10.1038/s41591-018-0012-z 29736026 PMC6076433 · DOI · Paper page
  83. [108]Strick R Strissel PL Baylin SB Chiappinelli KB Unraveling the molecular pathways of DNA-methylation inhibitors: human endogenous retroviruses induce the innate immune response in tumors Oncoimmunology. 2016 5 5 e1122160 10.1080/2162402X.2015.1122160 27467919 PMC4910697 · DOI
  84. [110]Cañadas I Thummalapalli R Kim JW Kitajima S Jenkins RW Christensen CL Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses Nat Med 2018 24 8 1143 1150 10.1038/s41591-018-0116-5 30038220 PMC6082722 · DOI
  85. [111]Sheng W LaFleur MW Nguyen TH Chen S Chakravarthy A Conway JR LSD1 ablation stimulates anti-tumor immunity and enables checkpoint blockade Cell 2018 174 3 549 563 10.1016/j.cell.2018.05.052 29937226 PMC6063761 · DOI · Paper page
  86. [112]Chaerkady R Harsha HC Nalli A Gucek M Vivekanandan P Akhtar J A quantitative proteomic approach for identification of potential biomarkers in hepatocellular carcinoma J Proteome Res 2008 7 10 4289 4298 10.1021/pr800197z 18715028 PMC3769105 · DOI
  87. [113]Lee JS Adler L Karathia H Carmel N Rabinovich S Auslander N Urea cycle dysregulation generates clinically relevant genomic and biochemical signatures Cell 2018 174 6 1559 1570 10.1016/j.cell.2018.07.019 30100185 PMC6225773 · DOI
  88. [114]Syed N Langer J Janczar K Singh P Lo Nigro C Lattanzio L Epigenetic status of argininosuccinate synthetase and argininosuccinate lyase modulates autophagy and cell death in glioblastoma Cell Death Dis 2013 4 e458 10.1038/cddis.2012.197 23328665 PMC3563985 · DOI
  89. [118]Garon EB Rizvi NA Hui R Leighl N Balmanoukian AS Eder JP Pembrolizumab for the treatment of non–small-cell lung cancer N Engl J Med 2015 372 21 2018 2028 10.1056/NEJMoa1501824 25891174 · DOI · Paper page
  90. [119]Eisenstein M Making cancer immunotherapy a surer bet Nature 2017 552 7685 S72 S73 10.1038/d41586-017-08704-5 32094674 · DOI
  91. [121]Ayers M Lunceford J Nebozhyn M Murphy E Loboda A Kaufman DR IFN-γ–related mRNA profile predicts clinical response to PD-1 blockade J Clin Invest 2017 127 8 2930 2940 10.1172/JCI91190 28650338 PMC5531419 · DOI · Paper page
  92. [122]Jiang P Gu S Pan D Fu J Sahu A Hu X Signatures of T cell dysfunction and exclusion predict cancer immunotherapy response Nat Med 2018 24 10 1550 1558 10.1038/s41591-018-0136-1 30127393 PMC6487502 · DOI · Paper page
  93. [123]Cristescu Razvan Mogg Robin Ayers Mark Albright Andrew Murphy Erin Yearley Jennifer Sher Xinwei Liu Xiao Qiao Lu Hongchao Nebozhyn Michael Zhang Chunsheng Lunceford Jared K. Joe Andrew Cheng Jonathan Webber Andrea L. Ibrahim Nageatte Plimack Elizabeth R. Ott Patrick A. Seiwert Tanguy Y. Ribas Antoni McClanahan Terrill K. Tomassini Joanne E. Loboda Andrey Kaufman David Pan-tumor genomic biomarkers for PD-1 checkpoint blockade–based immunotherapy Science 2018 362 6411 eaar3593 10.1126/science.aar3593 30309915 PMC6718162 · DOI · Paper page
  94. [124]Gandara DR Paul SM Kowanetz M Schleifman E Zou W Li Y Blood-based tumor mutational burden as a predictor of clinical benefit in non-small-cell lung cancer patients treated with atezolizumab Nat Med 2018 24 9 1441 1448 10.1038/s41591-018-0134-3 30082870 · DOI
  95. [125]Lee JH Long GV Menzies AM Lo S Guminski A Whitbourne K Association between circulating tumor dna and pseudoprogression in patients with metastatic melanoma treated with anti-programmed cell death 1 antibodies JAMA Oncol 2018 4 5 717 721 10.1001/jamaoncol.2017.5332 29423503 PMC5885201 · DOI
  96. [126]Chen G Huang AC Zhang W Zhang G Wu M Xu W Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response Nature 2018 560 7718 382 386 10.1038/s41586-018-0392-8 30089911 PMC6095740 · DOI · Paper page
  97. [129]Andre T, Lonardi S, Wong M, Lenz H-J, Gelsomino F, Aglietta M, et al. Nivolumab + ipilimumab combination in patients with DNA mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) metastatic colorectal cancer (mCRC): first report of the full cohort from CheckMate-142. J Clin Oncol. 2018. 10.1200/JCO.2018.36.4_suppl.553. · DOI
  98. [130]Hellmann MD Nathanson T Rizvi H Creelan BC Sanchez-Vega F Ahuja A Genomic features of response to combination immunotherapy in patients with advanced non-small-cell lung cancer Cancer Cell 2018 33 5 843 852 10.1016/j.ccell.2018.03.018 29657128 PMC5953836 · DOI · Paper page
  99. [131]Hellmann MD Callahan MK Awad MM Calvo E Ascierto PA Atmaca A 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 10.1016/j.ccell.2018.04.001 29731394 PMC6750707 · DOI
  100. [133]Donia M Fagone P Nicoletti F Andersen RS Høgdall E Straten PT BRAF inhibition improves tumor recognition by the immune system: potential implications for combinatorial therapies against melanoma involving adoptive T-cell transfer Oncoimmunology 2012 1 9 1476 1483 10.4161/onci.21940 23264894 PMC3525603 · DOI
  101. [134]Cooper ZA Frederick DT Ahmed Z Wargo JA Combining checkpoint inhibitors and BRAF-targeted agents against metastatic melanoma Oncoimmunology. 2013 2 5 e24320 10.4161/onci.24320 23762807 PMC3667913 · DOI
  102. [136]Li B Lalani AS Harding TC Luan B Koprivnikar K Tu GH Vascular endothelial growth factor blockade reduces intratumoral regulatory T cells and enhances the efficacy of a GM-CSF–secreting cancer immunotherapy Clin Cancer Res 2006 12 22 6808 6816 10.1158/1078-0432.CCR-06-1558 17121902 · DOI
  103. [137]Einstein DJ McDermott DF Combined blockade of vascular endothelial growth factor and programmed death 1 pathways in advanced kidney cancer Clin Adv Hematol Oncol 2017 15 6 478 488 28749908
  104. [138]Long Georgina V. Dummer Reinhard Hamid Omid Gajewski Thomas Caglevic Christian Dalle Stéphane Arance Ana Carlino Matteo S. Grob Jean-Jacques Kim Tae Min Demidov Lev V. Robert Caroline Larkin James M. G. Anderson James Maleski Janet E. Jones Mark M. Diede Scott J. Mitchell Tara C. Epacadostat (E) plus pembrolizumab (P) versus pembrolizumab alone in patients (pts) with unresectable or metastatic melanoma: Results of the phase 3 ECHO-301/KEYNOTE-252 study Journal of Clinical Oncology 2018 36 15_suppl 108 108 10.1200/JCO.2018.36.15_suppl.108 31221619 · DOI
  105. [140]Ribas A Hodi FS Callahan M Konto C Wolchok J Hepatotoxicity with combination of vemurafenib and ipilimumab N Engl J Med 2013 368 14 1365 1366 10.1056/NEJMc1302338 23550685 · DOI
  106. [141]Mazzone R Zwergel C Mai A Valente S Epi-drugs in combination with immunotherapy: a new avenue to improve anticancer efficacy Clin Epigenet 2017 9 59 10.1186/s13148-017-0358-y PMC5450222 28572863 · DOI
  107. [142]Li H Chiappinelli KB Guzzetta AA Easwaran H Yen R-WC Vatapalli R Immune regulation by low doses of the DNA methyltransferase inhibitor 5-azacitidine in common human epithelial cancers Oncotarget 2014 5 3 587 598 24583822 PMC3996658
  108. [143]Postow MA Callahan MK Barker CA Yamada Y Yuan J Kitano S Immunologic correlates of the abscopal effect in a patient with melanoma N Engl J Med 2012 366 10 925 931 10.1056/NEJMoa1112824 22397654 PMC3345206 · DOI
  109. [144]Formenti SC, Rudqvist N-P, Golden E, Cooper B, Wennerberg E, Lhuillier C, et al. Radiotherapy induces responses of lung cancer to CTLA-4 blockade. Nat Med. 2018. 10.1038/s41591-018-0232-2. PMC6286242 30397353 · DOI · Paper page
  110. [145]Ko EC Formenti SC Radiotherapy and checkpoint inhibitors: a winning new combination? Ther Adv Med Oncol 2018 10 1758835918768240 10.1177/1758835918768240 29662550 PMC5898659 · DOI
  111. [147]Zhang Q Bi J Zheng X Chen Y Wang H Wu W Blockade of the checkpoint receptor TIGIT prevents NK cell exhaustion and elicits potent anti-tumor immunity Nat Immunol 2018 19 7 723 732 10.1038/s41590-018-0132-0 29915296 · DOI
  112. [148]Bullock M Ren Y O’Neill C Gill A Aniss A Sywak M TERT promoter mutations are a major indicator of recurrence and death due to papillary thyroid carcinomas Clin Endocrinol 2016 85 2 283 290 10.1111/cen.12999 PMC5683578 26667986 · DOI
  113. [149]Polak P Kim J Braunstein LZ Karlic R Haradhavala NJ Tiao G A mutational signature reveals alterations underlying deficient homologous recombination repair in breast cancer Nat Genet 2017 49 10 1476 1486 10.1038/ng.3934 28825726 PMC7376751 · DOI · Paper page
  114. [150]Haratani K Hayashi H Chiba Y Kudo K Yonesaka K Kato R Association of immune-related adverse events with nivolumab efficacy in non-small-cell lung cancer JAMA Oncol. 2018 4 3 374 378 10.1001/jamaoncol.2017.2925 28975219 PMC6583041 · DOI · Paper page

Authors
Conway, J. R., Kofman, E., Mo, S. S., Elmarakeby, H., & Van Allen, E.
Affiliations
Broad Institute (US)
ORCID
Venue
Genome Medicine
Publisher
Springer Science and Business Media LLC
Published
2018-11-29
Volume
10
Issue
1
Pages
93-93
ISSN
1756-994X (ISSN-L)
DOI
10.1186/s13073-018-0605-7
PMC
PMC6264032
OpenAlex
W2902568381
Cited by
165
References
154
Citations by year
2026: 7 · 2025: 16 · 2024: 15 · 2023: 22 · 2022: 26 · 2021: 30 · 2020: 35 · 2019: 14
FWCI
2.30
Type
journal article
Language
en
Open access
Licence
Locations
  • Genome Medicine (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Greater South Information System
Funders
  • National Institutes of Health (5T32HG002295-15, R01CA227388)
  • Prostate Cancer Foundation (Prostate Cancer Foundation-V Foundation Challenge Award)
Topics
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
Keywords
immune checkpoint blockade, PD-1/PD-L1 blockade, CTLA-4 blockade, cancer immunotherapy response, tumor mutational burden, neoantigens, tumor microbiome, endogenous retroviruses, DNA repair deficiency, chromatin remodeling, PTEN loss, IDO1, TGF-beta, biomarkers, resistance mechanisms, precision oncology, combination therapy
MeSH terms
Animals, Humans, Immunotherapy, Neoplasms, Signal Transduction, Drug Resistance, Neoplasm, Genomics, Precision Medicine, B7-H1 Antigen, CTLA-4 Antigen

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review