CoChat
Sign Up
Cited by 273Cancer Immunotherapy and BiomarkersImmunotherapy and Immune ResponsesT-cell and B-cell Immunology

Therapeutically Increasing MHC-I Expression Potentiates Immune Checkpoint Blockade

Open access
Gu, Shengqing Stan, Zhang, Wubing, Wang, Xiaoqing, Jiang, Peng, Traugh, Nicole, Li, Ziyi, Meyer, Clifford, Stewig, Blair +25 more·2021·Cancer Discovery
DOI 10.1158/2159-8290.cd-20-0812PMC PMC8543117

Published version of a preprint

Open this paper in CoChat — free account

Abstract

Immune checkpoint blockade (ICB) therapy revolutionized cancer treatment, but many patients with impaired MHC-I expression remain refractory. Here, we combined FACS-based genome-wide CRISPR screens with a data-mining approach to identify drugs that can upregulate MHC-I without inducing PD-L1. CRISPR screening identified TRAF3, a suppressor of the NFκB pathway, as a negative regulator of MHC-I but not PD-L1. The Traf3-knockout gene expression signature is associated with better survival in ICB-naïve patients with cancer and better ICB response. We then screened for drugs with similar transcriptional effects as this signature and identified Second Mitochondria-derived Activator of Caspase (SMAC) mimetics. We experimentally validated that the SMAC mimetic birinapant upregulates MHC-I, sensitizes cancer cells to T cell–dependent killing, and adds to ICB efficacy. Our findings provide preclinical rationale for treating tumors expressing low MHC-I expression with SMAC mimetics to enhance sensitivity to immunotherapy. The approach used in this study can be generalized to identify other drugs that enhance immunotherapy efficacy. Significance: MHC-I loss or downregulation in cancer cells is a major mechanism of resistance to T cell–based immunotherapies. Our study reveals that birinapant may be used for patients with low baseline MHC-I to enhance ICB response. This represents promising immunotherapy opportunities given the biosafety profile of birinapant from multiple clinical trials. This article is highlighted in the In This Issue feature, p. 1307

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 · 10.1158/2159-8290.cd-20-0812

Cites

18 of 18 references verified0 citation errors · 0 not checkable

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?

  • Various critical transcription factors, including HIF-1α, c-MYC, NF-kB, STAT3, c-JUN, and miR-138-5p, have been shown to transcriptionally regulate PD-L1 expression.

    “Various critical transcription factors, including HIF-1α, c-MYC, NF-kB, STAT3, c-JUN, and miR-138-5p have been shown to transcriptionally regulate PD-L1 expression25–30.”

    From PRDM1/BLIMP1 induces cancer immune evasion by modulating the USP22-SPI1-PD-L1 axis in hepatocellular carcinoma cells (2022) · cites this paper as [27]

    The Introduction (page unavailable) says IFNγ induces PD-L1, but does not identify the listed factors as its transcriptional regulators. The Results section on TRAF3 depletion discusses NF-κB regulation of MHC-I and reports no change in PD-L1 transcription after TRAF3 knockout. Searches for the listed factors and PD-L1 transcriptional regulation found no passage establishing the attributed claim. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

Self-check

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

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

Cites

Flagged first, then by citations

Research works printed but not linked: 77

  1. [1]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: 2443– 54. 22658127 PMC3544539
  2. [2]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: 2189– 99. 25409260 PMC4315319
  3. [4]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: 711– 23. 20525992 PMC3549297
  4. [5]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: 311– 9. 25482239 PMC4348009
  5. [6]Powles T, Eder JP, Fine GD, Braiteh FS, Loriot Y, Cruz C, MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature. 2014; 515: 558– 62. 25428503
  6. [8]McDermott DF, Sosman JA, Sznol M, Massard C, Gordon MS, Hamid O, Atezolizumab, an Anti-Programmed Death-Ligand 1 Antibody, in Metastatic Renal Cell Carcinoma: Long-Term Safety, Clinical Activity, and Immune Correlates From a Phase Ia Study. J Clin Oncol. 2016; 34: 833– 42. 26755520
  7. [9]Sharma P, Hu-Lieskovan S, Wargo JA, Ribas A. Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy. Cell. 2017; 168: 707– 23. 28187290 PMC5391692
  8. [12]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. New England Journal of Medicine. 2016; 375: 819– 29. PMC5007206 27433843
  9. [13]Rodig SJ, Gusenleitner D, Jackson DG, Gjini E, Giobbie-Hurder A, Jin C, MHC proteins confer differential sensitivity to CTLA-4 and PD-1 blockade in untreated metastatic melanoma. Sci Transl Med. 2018; 10: 1– 13. 30021886
  10. [14]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: 582– 7. 29217585 PMC6057471
  11. [15]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: 1259– 71. e11. 29107330 PMC5720478
  12. [18]Patel SJ, Sanjana NE, Kishton RJ, Eidizadeh A, Vodnala SK, Cam M, Identification of essential genes for cancer immunotherapy. Nature. 2017; 548: 537– 42. 28783722 PMC5870757
  13. [20]Sumimoto H, Imabayashi F, Iwata T, Kawakami Y. The BRAF-MAPK signaling pathway is essential for cancer-immune evasion in human melanoma cells. J Exp Med. 2006; 203: 1651– 6. 16801397 PMC2118331
  14. [21]Spranger S, Bao R, Gajewski TF. Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity. Nature. 2015; 523: 231– 5. 25970248
  15. [23]Peng W, Chen JQ, Liu C, Malu S, Creasy C, Tetzlaff MT, Loss of PTEN Promotes Resistance to T Cell–Mediated Immunotherapy. Cancer Discov. American Association for Cancer Research; 2016; 6: 202– 16. PMC4744499 26645196
  16. [25]Rosenthal R, Cadieux EL, Salgado R, Bakir MA, Moore DA, Hiley CT, Neoantigen-directed immune escape in lung cancer evolution. Nature. 2019; 567: 479– 85. 30894752 PMC6954100
  17. [26]Garrido F, Aptsiauri N, Doorduijn EM, Garcia Lora AM, van Hall T. The urgent need to recover MHC class I in cancers for effective immunotherapy. Curr Opin Immunol. 2016; 39: 44– 51. 26796069 PMC5138279
  18. [27]Davis MM, Boniface JJ, Reich Z, Lyons D, Hampl J, Arden B, Ligand recognition by alpha beta T cell receptors. Annu Rev Immunol. 1998; 16: 523– 44. 9597140
  19. [28]Verma V, Shrimali RK, Ahmad S, Dai W, Wang H, Lu S, PD-1 blockade in subprimed CD8 cells induces dysfunctional PD-1CD38 cells and anti-PD-1 resistance. Nat Immunol. 2019; 20: 1231– 43. 31358999 PMC7472661
  20. [29]van den Elsen PJ, Holling TM, Kuipers HF, van der Stoep N. Transcriptional regulation of antigen presentation. Current Opinion in Immunology. 2004; 16: 67– 75. 14734112
  21. [30]Zhou F. Molecular Mechanisms of IFN-γ to Up-Regulate MHC Class I Antigen Processing and Presentation. International Reviews of Immunology. 2009; 28: 239– 60. 19811323
  22. [31]Parker BS, Rautela J, Hertzog PJ. Antitumour actions of interferons: implications for cancer therapy. Nat Rev Cancer. 2016; 16: 131– 44. 26911188
  23. [32]Benci JL, Johnson LR, Choa R, Xu Y, Qiu J, Zhou Z, Opposing Functions of Interferon Coordinate Adaptive and Innate Immune Responses to Cancer Immune Checkpoint Blockade. Cell. 2019; 178: 933– 48. e14. 31398344 PMC6830508
  24. [34]Burr ML, Sparbier CE, Chan Y-C, Williamson JC, Woods K, Beavis PA, CMTM6 maintains the expression of PD-L1 and regulates anti-tumour immunity. Nature. 2017; 549: 101– 5. 28813417 PMC5706633
  25. [35]Mezzadra R, Sun C, Jae LT, Gomez-Eerland R, de Vries E, Wu W, Identification of CMTM6 and CMTM4 as PD-L1 protein regulators. Nature. 2017; 549: 106– 10. 28813410 PMC6333292
  26. [36]Burr ML, Sparbier CE, Chan KL, Chan Y-C, Kersbergen A, Lam EYN, An Evolutionarily Conserved Function of Polycomb Silences the MHC Class I Antigen Presentation Pathway and Enables Immune Evasion in Cancer. Cancer Cell. 2019; 36: 385– 401. 31564637 PMC6876280
  27. [38]Goel S, DeCristo MJ, Watt AC, BrinJones H, Sceneay J, Li BB, CDK4/6 inhibition triggers anti-tumour immunity. Nature. 2017; 548: 471– 5. 28813415 PMC5570667
  28. [40]Medina BD, Liu M, Vitiello GA, Seifert AM, Zeng S, Bowler T, Oncogenic kinase inhibition limits Batf3-dependent dendritic cell development and antitumor immunity. J Exp Med. 2019; 216: 1359– 76. 31000683 PMC6547861
  29. [41]Li W, Xu H, Xiao T, Cong L, Love MI, Zhang F, MAGeCK enables robust identification of essential genes from genome-scale CRISPR/Cas9 knockout screens. Genome Biol. 2014; 15: 554. 25476604 PMC4290824
  30. [42]Wang B, Wang M, Zhang W, Xiao T, Chen C-H, Wu A, Integrative analysis of pooled CRISPR genetic screens using MAGeCKFlute. Nat Protoc. 2019; 14: 756– 80. 30710114 PMC6862721
  31. [43]Luo B, Cheung HW, Subramanian A, Sharifnia T, Okamoto M, Yang X, Highly parallel identification of essential genes in cancer cells. Proc Natl Acad Sci U S A. 2008; 105: 20380– 5. 19091943 PMC2629277
  32. [44]Zhou L, Mudianto T, Ma X, Riley R, Uppaluri R. Targeting EZH2 Enhances Antigen Presentation, Antitumor Immunity, and Circumvents Anti-PD-1 Resistance in Head and Neck Cancer. Clin Cancer Res. 2020; 26: 290– 300. 31562203 PMC6942613
  33. [45]Häcker H, Tseng P-H, Karin M. Expanding TRAF function: TRAF3 as a tri-faced immune regulator. Nat Rev Immunol. 2011; 11: 457– 68. 21660053
  34. [46]Jongsma MLM, Guarda G, Spaapen RM. The regulatory network behind MHC class I expression. Mol Immunol. 2019; 113: 16– 21. 29224918
  35. [47]Spel L, Nieuwenhuis J, Haarsma R, Stickel E, Bleijerveld OB, Altelaar M, Nedd4-Binding Protein 1 and TNFAIP3-Interacting Protein 1 Control MHC-1 Display in Neuroblastoma. Cancer Res. 2018; 78: 6621– 31. 30213788
  36. [48]Zarnegar BJ, Wang Y, Mahoney DJ, Dempsey PW, Cheung HH, He J, Noncanonical NF-κB activation requires coordinated assembly of a regulatory complex of the adaptors cIAP1, cIAP2, TRAF2 and TRAF3 and the kinase NIK. Nature Immunology. 2008; 9: 1371– 8. 18997794 PMC2676931
  37. [49]Vallabhapurapu S, Matsuzawa A, Zhang W, Tseng P-H, Keats JJ, Wang H, Nonredundant and complementary functions of TRAF2 and TRAF3 in a ubiquitination cascade that activates NIK-dependent alternative NF-κB signaling. Nature Immunology. 2008; 9: 1364– 70. 18997792 PMC2671996
  38. [50]Bista P, Zeng W, Ryan S, Bailly V, Browning JL, Lukashev ME. TRAF3 Controls Activation of the Canonical and Alternative NFκB by the Lymphotoxin Beta Receptor. Journal of Biological Chemistry. 2010; 285: 12971– 8. PMC2857099 20185819
  39. [51]Li S, Wan C, Zheng R, Fan J, Dong X, Meyer CA, Cistrome-GO: a web server for functional enrichment analysis of transcription factor ChIP-seq peaks. Nucleic Acids Res. 2019; 47: W206– 11. 31053864 PMC6602521
  40. [52]Heinz S, Benner C, Spann N, Bertolino E, Lin YC, Laslo P, Simple Combinations of Lineage-Determining Transcription Factors Prime cis-Regulatory Elements Required for Macrophage and B Cell Identities. Molecular Cell. 2010; 38: 576– 89. 20513432 PMC2898526
  41. [53]Mei S, Qin Q, Wu Q, Sun H, Zheng R, Zang C, Cistrome Data Browser: a data portal for ChIP-Seq and chromatin accessibility data in human and mouse. Nucleic Acids Res. 2017; 45: D658– 62. 27789702 PMC5210658
  42. [54]Zheng R, Wan C, Mei S, Qin Q, Wu Q, Sun H, Cistrome Data Browser: expanded datasets and new tools for gene regulatory analysis. Nucleic Acids Res. 2019; 47: D729– 35. 30462313 PMC6324081
  43. [55]Layer RM, Pedersen BS, DiSera T, Marth GT, Gertz J, Quinlan AR. GIGGLE: a search engine for large-scale integrated genome analysis. Nat Methods. 2018; 15: 123– 6. 29309061 PMC5872823
  44. [56]Gilmore TD. Introduction to NF-κB: players, pathways, perspectives. Oncogene. 2006; 25: 6680– 4. 17072321
  45. [57]Vallabhapurapu S, Karin M. Regulation and Function of NF-κB Transcription Factors in the Immune System. Annual Review of Immunology. 2009; 27: 693– 733. 19302050
  46. [58]Sun S-C. The non-canonical NF-κB pathway in immunity and inflammation. Nat Rev Immunol. 2017; 17: 545– 58. 28580957 PMC5753586
  47. [59]Hayden MS, Ghosh S. Shared Principles in NF-κB Signaling. Cell. 2008; 132: 344– 62. 18267068
  48. [60]Zhao B, Barrera LA, Ersing I, Willox B, Schmidt SCS, Greenfeld H, The NF-κB genomic landscape in lymphoblastoid B cells. Cell Rep. 2014; 8: 1595– 606. 25159142 PMC4163118
  49. [62]Iannetti A, Ledoux AC, Tudhope SJ, Sellier H, Zhao B, Mowla S, Regulation of p53 and Rb links the alternative NF-κB pathway to EZH2 expression and cell senescence. PLoS Genet. 2014; 10: e1004642. PMC4177746 25255445
  50. [63]Such L, Zhao F, Liu D, Thier B, Le-Trilling VTK, Sucker A, Targeting the innate immunoreceptor RIG-I overcomes melanoma-intrinsic resistance to T cell immunotherapy. Journal of Clinical Investigation. 2020; 130: 4266– 81. PMC7410049 32427578
  51. [64]Kalbasi A, Tariveranmoshabad M, Hakimi K, Kremer S, Campbell KM, Funes JM, Uncoupling interferon signaling and antigen presentation to overcome immunotherapy resistance due to JAK1 loss in melanoma. Sci Transl Med. 2020; 12: eabb0152. PMC8053376 33055240
  52. [65]Lanier LL. NK cell recognition. Annu Rev Immunol. 2005; 23: 225– 74. 15771571
  53. [66]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: 1550– 8. 30127393 PMC6487502
  54. [67]Scheper W, Kelderman S, Fanchi LF, Linnemann C, Bendle G, de Rooij MAJ, Low and variable tumor reactivity of the intratumoral TCR repertoire in human cancers. Nat Med. 2019; 25: 89– 94. 30510250
  55. [68]Font-Tello A, Kesten N, Xie Y, Taing L, Varešlija D, Young LS, FiTAc-seq: fixed-tissue ChIP-seq for H3K27ac profiling and super-enhancer analysis of FFPE tissues. Nature Protocols. 2020; 15: 2503– 18. 32591768
  56. [69]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: 819– 29. 27433843 PMC5007206
  57. [71]Gide TN, Quek C, Menzies AM, Tasker AT, Shang P, Holst J, Distinct Immune Cell Populations Define Response to Anti-PD-1 Monotherapy and Anti-PD-1/Anti-CTLA-4 Combined Therapy. Cancer Cell. 2019; 35: 238– 55. e6. 30753825
  58. [72]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: 544– 8. 29443960 PMC6028240
  59. [73]Zhou L, Mudianto T, Ma X, Riley R, Uppaluri R. Targeting EZH2 Enhances Antigen Presentation, Antitumor Immunity, and Circumvents Anti–PD-1 Resistance in Head and Neck Cancer. Clinical Cancer Research. 2020; 26: 290– 300. 31562203 PMC6942613
  60. [74]Vince JE, Wei-Lynn Wong W, Khan N, Feltham R, Chau D, Ahmed AU, IAP Antagonists Target cIAP1 to Induce TNFα-Dependent Apoptosis. Cell. 2007; 131: 682– 93. 18022363
  61. [76]Li B, Severson E, Pignon J-C, Zhao H, Li T, Novak J, Comprehensive analyses of tumor immunity: implications for cancer immunotherapy. Genome Biol. 2016; 17: 174. 27549193 PMC4993001
  62. [77]Li T, Fan J, Wang B, Traugh N, Chen Q, Liu JS, TIMER: A Web Server for Comprehensive Analysis of Tumor-Infiltrating Immune Cells. Cancer Res. 2017; 77: e108– 10. 29092952 PMC6042652
  63. [78]Gu SS, Wang X, Hu X, Jiang P, Li Z, Traugh N, Clonal tracing reveals diverse patterns of response to immune checkpoint blockade. Genome Biol. 2020; 21: 263. 33059736 PMC7559192
  64. [79]Bertrand MJM, Milutinovic S, Dickson KM, Ho WC, Boudreault A, Durkin J, cIAP1 and cIAP2 facilitate cancer cell survival by functioning as E3 ligases that promote RIP1 ubiquitination. Mol Cell. 2008; 30: 689– 700. 18570872
  65. [80]Beug ST, Beauregard CE, Healy C, Sanda T, St-Jean M, Chabot J, Smac mimetics synergize with immune checkpoint inhibitors to promote tumour immunity against glioblastoma. Nat Commun. 2017; 8: 14278. PMC5330852 28198370
  66. [81]Sun D, Wang J, Han Y, Dong X, Zheng R, Ge J, TISCH: a comprehensive web resource enabling interactive single-cell transcriptome visualization of tumor microenvironment. Nucleic Acids Res. 2021; 49(D1): D1420– 30. 33179754 PMC7778907
  67. [82]Zhang H, Christensen CL, Dries R, Oser MG, Deng J, Diskin B, CDK7 Inhibition Potentiates Genome Instability Triggering Anti-tumor Immunity in Small Cell Lung Cancer. Cancer Cell. 2020; 37: 37– 54. e9. 31883968 PMC7277075
  68. [83]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: 279ra41. PMC4765379 25787767
  69. [85]Aran D, Sirota M, Butte AJ. Systematic pan-cancer analysis of tumour purity. Nat Commun. 2015; 6: 8971. 26634437 PMC4671203
  70. [86]Li B, Li JZ. A general framework for analyzing tumor subclonality using SNP array and DNA sequencing data. Genome Biol. 2014; 15: 473. 25253082 PMC4203890
  71. [87]Xiao T, Li W, Wang X, Xu H, Yang J, Wu Q, Estrogen-regulated feedback loop limits the efficacy of estrogen receptor-targeted breast cancer therapy. Proc Natl Acad Sci U S A. 2018; 115: 7869– 78. 29987050 PMC6077722
  72. [88]Sanjana NE, Shalem O, Zhang F. Improved vectors and genome-wide libraries for CRISPR screening. Nat Methods. 2014; 11: 783– 4. 25075903 PMC4486245
  73. [90]Gu S, Sayad A, Chan G, Yang W, Lu Z, Virtanen C, SHP2 is required for BCR-ABL1-induced hematologic neoplasia. Leukemia. 2018; 32: 203– 13. 28804122 PMC6005183
  74. [91]Qin Q, Mei S, Wu Q, Sun H, Li L, Taing L, ChiLin: a comprehensive ChIP-seq and DNase-seq quality control and analysis pipeline. BMC Bioinformatics. 2016; 17: 404. 27716038 PMC5048594
  75. [92]Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009; 25: 1754– 60. 19451168 PMC2705234
  76. [93]Zhang Y, Liu T, Meyer CA, Eeckhoute J, Johnson DS, Bernstein BE, Model-based analysis of ChIP-Seq (MACS). Genome Biol. 2008; 9: R137. PMC2592715 18798982
  77. [94]Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014; 15: 550. 25516281 PMC4302049

Cited by

Sorted by citations

Authors
Gu, S. S., Zhang, W., Wang, X., Jiang, P., Traugh, N., Li, Z., Meyer, C., Stewig, B., Xie, Y., Bu, X., Manos, M. P., Font-Tello, A., Gjini, E., Lako, A., Lim, K., Conway, J., Tewari, A. K., Zeng, Z., Sahu, A. D., Tokheim, C., Weirather, J. L., Fu, J., Zhang, Y., Kroger, B., Liang, J. H., Cejas, P., Freeman, G. J., Rodig, S., Long, H. W., Gewurz, B. E., Hodi, F. S., Brown, M., & Liu, X. S.
Affiliations
  • Harvard University (US)
  • Tongji University (CN)
  • Dana-Farber Cancer Institute (US)
  • National Cancer Institute (US)
  • 6Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • The University of Texas Southwestern Medical Center (US)
  • Brigham and Women's Hospital (US)
Corresponding author
  • Brown, Myles
  • Liu, X. Shirley
ORCID
Venue
Cancer Discovery
Publisher
American Association for Cancer Research (AACR)
Published
2021-02-15
Volume
11
Issue
6
Pages
1524-1541
ISSN
  • 2159-8274 (ISSN-L)
  • 2159-8290
DOI
10.1158/2159-8290.cd-20-0812
PMC
PMC8543117
OpenAlex
W3131183594
Cited by
273
References
18
Citations by year
2026: 37 · 2025: 59 · 2024: 72 · 2023: 51 · 2022: 43 · 2021: 11
FWCI
16.30
Type
journal article
Language
en
Open access
Locations
  • Cancer Discovery (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
NIH (R01CA234018, R01AI137337, P50CA101942-12, P50CA206963)
Topics
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords
MHC class I upregulation, immune checkpoint blockade, TRAF3, NF-κB signaling, IAP antagonists, birinapant, PD-L1, cancer immunotherapy resistance, CRISPR screen, drug repurposing
MeSH terms
Immune Checkpoint Inhibitors, Humans, Immunotherapy, Neoplasms, Histocompatibility Antigens Class I, Gene Expression Profiling, Data Mining, Tumor Microenvironment, B7-H1 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