Clinical response to nivolumab in an INI1-deficient pediatric chordoma correlates with immunogenic recognition of brachyury.
Journal
NPJ precision oncology
ISSN: 2397-768X
Titre abrégé: NPJ Precis Oncol
Pays: England
ID NLM: 101708166
Informations de publication
Date de publication:
20 Dec 2021
20 Dec 2021
Historique:
received:
06
04
2021
accepted:
22
10
2021
entrez:
21
12
2021
pubmed:
22
12
2021
medline:
22
12
2021
Statut:
epublish
Résumé
Poorly differentiated chordoma (PDC) is a recently recognized subtype of chordoma characterized by expression of the embryonic transcription factor, brachyury, and loss of INI1. PDC primarily affects children and is associated with a poor prognosis and limited treatment options. Here we describe the molecular and immune tumour microenvironment profiles of two paediatric PDCs produced using whole-genome, transcriptome and whole-genome bisulfite sequencing (WGBS) and multiplex immunohistochemistry. Our analyses revealed the presence of tumour-associated immune cells, including CD8+ T cells, and expression of the immune checkpoint protein, PD-L1, in both patient samples. Molecular profiling provided the rationale for immune checkpoint inhibitor (ICI) therapy, which resulted in a clinical and radiographic response. A dominant T cell receptor (TCR) clone specific for a brachyury peptide-MHC complex was identified from bulk RNA sequencing, suggesting that targeting of the brachyury tumour antigen by tumour-associated T cells may underlie this clinical response to ICI. Correlative analysis with rhabdoid tumours, another INI1-deficient paediatric malignancy, suggests that a subset of tumours may share common immune phenotypes, indicating the potential for a therapeutically targetable subgroup of challenging paediatric cancers.
Identifiants
pubmed: 34931022
doi: 10.1038/s41698-021-00238-4
pii: 10.1038/s41698-021-00238-4
pmc: PMC8688516
doi:
Types de publication
Journal Article
Langues
eng
Pagination
103Subventions
Organisme : Genome British Columbia
ID : 202SEQ
Organisme : Genome British Columbia
ID : 212SEQ
Organisme : Genome British Columbia
ID : B20POG
Organisme : Genome British Columbia
ID : 202SEQ
Organisme : Genome British Columbia
ID : 212SEQ
Organisme : Genome British Columbia
ID : B20POG
Organisme : Canada Foundation for Innovation (Fondation canadienne pour l'innovation)
ID : 33408
Organisme : Canada Foundation for Innovation (Fondation canadienne pour l'innovation)
ID : 20070
Organisme : Canada Foundation for Innovation (Fondation canadienne pour l'innovation)
ID : 30981
Organisme : Canada Foundation for Innovation (Fondation canadienne pour l'innovation)
ID : 30198
Organisme : Canada Foundation for Innovation (Fondation canadienne pour l'innovation)
ID : 36239
Organisme : Canada Foundation for Innovation (Fondation canadienne pour l'innovation)
ID : 36239
Organisme : Canada Foundation for Innovation (Fondation canadienne pour l'innovation)
ID : 20070
Organisme : Canada Foundation for Innovation (Fondation canadienne pour l'innovation)
ID : 30981
Organisme : Canada Foundation for Innovation (Fondation canadienne pour l'innovation)
ID : 33408
Organisme : Canada Foundation for Innovation (Fondation canadienne pour l'innovation)
ID : 35444
Organisme : Canada Foundation for Innovation (Fondation canadienne pour l'innovation)
ID : 30981
Organisme : Genome Canada (Génome Canada)
ID : 12002
Organisme : Genome Canada (Génome Canada)
ID : 12002
Informations de copyright
© 2021. Crown.
Références
Yeter, H. G., Kosemehmetoglu, K. & Soylemezoglu, F. Poorly differentiated chordoma: review of 53 cases. APMIS 127, 607–615 (2019).
pubmed: 31243811
doi: 10.1111/apm.12978
Hasselblatt, M. et al. Poorly differentiated chordoma with SMARCB1/INI1 loss: a distinct molecular entity with dismal prognosis. Acta Neuropathol. 132, 149–151 (2016).
pubmed: 27067307
doi: 10.1007/s00401-016-1574-9
Shih, A. R. et al. Clinicopathologic characteristics of poorly differentiated chordoma. Mod. Pathol. 31, 1237–1245 (2018).
pubmed: 29483606
doi: 10.1038/s41379-018-0002-1
Antonelli, M. et al. SMARCB1/INI1 involvement in pediatric chordoma: a mutational and immunohistochemical analysis. Am. J. Surg. Pathol. 41, 56–61 (2017).
pubmed: 27635948
doi: 10.1097/PAS.0000000000000741
Jaber, O. I. & Ashhab, M. A. Metastatic poorly differentiated chordoma: the eyes do not see what the mind does not know. Autops. Case Rep. 9, e2019120 (2019).
pubmed: 31641661
pmcid: 6771453
doi: 10.4322/acr.2019.120
Vaddepally, R. K., Kharel, P., Pandey, R., Garje, R. & Chandra, A. B. Review of indications of FDA-approved immune checkpoint inhibitors per NCCN guidelines with the level of evidence. Cancers 12, 738 (2020).
pmcid: 7140028
doi: 10.3390/cancers12030738
Geoerger, B. et al. Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial. Lancet Oncol. 21, 121–133 (2020).
pubmed: 31812554
doi: 10.1016/S1470-2045(19)30671-0
Davis, K. L. et al. Nivolumab in children and young adults with relapsed or refractory solid tumours or lymphoma (ADVL1412): a multicentre, open-label, single-arm, phase 1-2 trial. Lancet Oncol. 21, 541–550 (2020).
pubmed: 32192573
pmcid: 7255545
doi: 10.1016/S1470-2045(20)30023-1
Geoerger, B. et al. Atezolizumab for children and young adults with previously treated solid tumours, non-Hodgkin lymphoma, and Hodgkin lymphoma (iMATRIX): a multicentre phase 1-2 study. Lancet Oncol. 21, 134–144 (2020).
pubmed: 31780255
doi: 10.1016/S1470-2045(19)30693-X
Bourdeaut, F., Thaku, M. D., Bergthold, G. & Karski, E. Atrt-11. Marked response to atezolizumab in a patient with rhabdoid tumor: a case study from the imatrix-atezolizumab trial. Neuro-Oncol. 19, iv3 (2017).
pmcid: 5474990
doi: 10.1093/neuonc/nox083.010
Jelinic, P. et al. Immune-active microenvironment in small cell carcinoma of the ovary, hypercalcemic type: rationale for immune checkpoint blockade. J. Natl Cancer Inst. 110, 787–790 (2018).
pubmed: 29365144
pmcid: 6037122
doi: 10.1093/jnci/djx277
Wu, X. et al. Response of metastatic chordoma to the immune checkpoint inhibitor pembrolizumab: a case report. Front. Oncol. 10, 565945 (2020).
pubmed: 33392069
pmcid: 7774333
doi: 10.3389/fonc.2020.565945
Forrest, S. J. et al. Genomic and immunologic characterization of INI1-deficient pediatric cancers. Clin. Cancer Res. 26, 2882–2890 (2020).
pubmed: 32122923
doi: 10.1158/1078-0432.CCR-19-3089
Leruste, A. et al. Clonally expanded T cells reveal immunogenicity of rhabdoid tumors. Cancer Cell 36, 597.e8–612.e8 (2019).
doi: 10.1016/j.ccell.2019.10.008
Miao, D. et al. Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma. Science 359, 801–806 (2018).
pubmed: 29301960
pmcid: 6035749
doi: 10.1126/science.aan5951
Abro, B. et al. Tumor mutation burden, DNA mismatch repair status and checkpoint immunotherapy markers in primary and relapsed malignant rhabdoid tumors. Pathol. Res. Pract. 215, 152395 (2019).
pubmed: 31047727
doi: 10.1016/j.prp.2019.03.023
Chun, H.-J. E. et al. Identification and analyses of extra-cranial and cranial rhabdoid tumor molecular subgroups reveal tumors with cytotoxic T cell infiltration. Cell Rep. 29, 2338.e7–2354.e7 (2019).
doi: 10.1016/j.celrep.2019.10.013
Cancer Genome Atlas Research Network et al. Comprehensive and integrated genomic characterization of adult soft tissue sarcomas. Cell 171, 950.e28–965.e28 (2017).
Pleasance, E. et al. Pan-cancer analysis of advanced patient tumors reveals interactions between therapy and genomic landscapes. Nat. Cancer 1, 452–468 (2020).
pubmed: 35121966
doi: 10.1038/s43018-020-0050-6
Pan, D. et al. A major chromatin regulator determines resistance of tumor cells to T cell-mediated killing. Science 359, 770–775 (2018).
pubmed: 29301958
pmcid: 5953516
doi: 10.1126/science.aao1710
Newman, A. M. et al. Robust enumeration of cell subsets from tissue expression profiles. Nat. Methods 12, 453–457 (2015).
pubmed: 25822800
pmcid: 4739640
doi: 10.1038/nmeth.3337
Pender, A. et al. Genome and transcriptome biomarkers of response to immune checkpoint inhibitors in advanced solid tumors. Clin. Cancer Res. 27, 202–212 (2021).
pubmed: 33020056
doi: 10.1158/1078-0432.CCR-20-1163
Feng, X. et al. Therapeutic implication of genomic landscape of adult metastatic sarcoma. JCO Precis. Oncol. https://doi.org/10.1200/PO.18.00325 (2019).
Versteege, I. et al. Truncating mutations of hSNF5/INI1 in aggressive paediatric cancer. Nature 394, 203–206 (1998).
pubmed: 9671307
doi: 10.1038/28212
Biegel, J. A. et al. The role of INI1 and the SWI/SNF complex in the development of rhabdoid tumors: meeting summary from the workshop on childhood atypical teratoid/rhabdoid tumors. Cancer Res. 62, 323–328 (2002).
pubmed: 11782395
Griss, J. et al. B cells sustain inflammation and predict response to immune checkpoint blockade in human melanoma. Nat. Commun. 10, 4186 (2019).
pubmed: 31519915
pmcid: 6744450
doi: 10.1038/s41467-019-12160-2
Treffers, L. W. et al. IgA-mediated killing of tumor cells by neutrophils is enhanced by CD47-SIRPα checkpoint inhibition. Cancer Immunol. Res. 8, 120–130 (2020).
pubmed: 31690649
doi: 10.1158/2326-6066.CIR-19-0144
Samstein, R. M. et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat. Genet. 51, 202–206 (2019).
pubmed: 30643254
pmcid: 6365097
doi: 10.1038/s41588-018-0312-8
Goodman, A. M. et al. Tumor mutational burden as an independent predictor of response to immunotherapy in diverse cancers. Mol. Cancer Ther. 16, 2598–2608 (2017).
pubmed: 28835386
pmcid: 5670009
doi: 10.1158/1535-7163.MCT-17-0386
Bolotin, D. A. et al. MiXCR: software for comprehensive adaptive immunity profiling. Nat. Methods 12, 380–381 (2015).
pubmed: 25924071
doi: 10.1038/nmeth.3364
Palena, C. et al. The human T-box mesodermal transcription factor Brachyury is a candidate target for T-cell-mediated cancer immunotherapy. Clin. Cancer Res. 13, 2471–2478 (2007).
pubmed: 17438107
doi: 10.1158/1078-0432.CCR-06-2353
Tucker, J. A. et al. Identification and characterization of a cytotoxic T-lymphocyte agonist epitope of brachyury, a transcription factor involved in epithelial to mesenchymal transition and metastasis. Cancer Immunol. Immunother. CII 63, 1307–1317 (2014).
pubmed: 25186612
doi: 10.1007/s00262-014-1603-2
DeMaria, P. J. et al. A randomized, double-blind, phase II clinical trial of GI-6301 (yeast-brachyury vaccine) versus placebo in combination with standard of care definitive radiotherapy in locally advanced, unresectable, chordoma. J. Clin. Oncol. 38, 11527–11527 (2020).
doi: 10.1200/JCO.2020.38.15_suppl.11527
Henon, C. et al. Long lasting major response to pembrolizumab in a thoracic malignant rhabdoid-like SMARCA4-deficient tumor. Ann. Oncol. 30, 1401–1403 (2019).
pubmed: 31114851
doi: 10.1093/annonc/mdz160
Blay, J.-Y. et al. 1619O High clinical benefit rates of single agent pembrolizumab in selected rare sarcoma histotypes: first results of the AcSé Pembrolizumab study. Ann. Oncol. 31, S972 (2020).
doi: 10.1016/j.annonc.2020.08.1845
Theruvath, J. et al. Locoregionally administered B7-H3-targeted CAR T cells for treatment of atypical teratoid/rhabdoid tumors. Nat. Med. 26, 712–719 (2020).
pubmed: 32341579
pmcid: 7992505
doi: 10.1038/s41591-020-0821-8
Terry, R. L. et al. Immune profiling of pediatric solid tumors. J. Clin. Investig. 130, 3391–3402 (2020).
pubmed: 32538896
pmcid: 7324195
doi: 10.1172/JCI137181
Plesca, I. et al. Characteristics of tumor-infiltrating lymphocytes prior to and during immune checkpoint inhibitor therapy. Front. Immunol. 11, 364 (2020).
pubmed: 32194568
pmcid: 7064638
doi: 10.3389/fimmu.2020.00364
Uryvaev, A., Passhak, M., Hershkovits, D., Sabo, E. & Bar-Sela, G. The role of tumor-infiltrating lymphocytes (TILs) as a predictive biomarker of response to anti-PD1 therapy in patients with metastatic non-small cell lung cancer or metastatic melanoma. Med. Oncol. 35, 25 (2018).
pubmed: 29388007
doi: 10.1007/s12032-018-1080-0
Cristescu, R. et al. Pan-tumor genomic biomarkers for PD-1 checkpoint blockade–based immunotherapy. Science 362, eaar3593 (2018).
pubmed: 30309915
pmcid: 6718162
doi: 10.1126/science.aar3593
Tumeh, P. C. et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515, 568–571 (2014).
pubmed: 25428505
pmcid: 4246418
doi: 10.1038/nature13954
Coulie, P. G., Van den Eynde, B. J., van der Bruggen, P. & Boon, T. Tumour antigens recognized by T lymphocytes: at the core of cancer immunotherapy. Nat. Rev. Cancer 14, 135–146 (2014).
pubmed: 24457417
doi: 10.1038/nrc3670
Sahin, U. et al. An RNA vaccine drives immunity in checkpoint-inhibitor-treated melanoma. Nature 585, 107–112 (2020).
pubmed: 32728218
doi: 10.1038/s41586-020-2537-9
Migliorini, D. et al. First report of clinical responses to immunotherapy in 3 relapsing cases of chordoma after failure of standard therapies. Oncoimmunology 6, e1338235 (2017).
pubmed: 28919999
pmcid: 5593713
doi: 10.1080/2162402X.2017.1338235
Mathios, D. et al. PD-1, PD-L1, PD-L2 expression in the chordoma microenvironment. J. Neurooncol. 121, 251–259 (2015).
pubmed: 25349132
doi: 10.1007/s11060-014-1637-5
Feng, Y. et al. Expression of programmed cell death ligand 1 (PD-L1) and prevalence of tumor-infiltrating lymphocytes (TILs) in chordoma. Oncotarget 6, 11139–11149 (2015).
pubmed: 25871477
pmcid: 4484445
doi: 10.18632/oncotarget.3576
Fujii, R. et al. Enhanced killing of chordoma cells by antibody-dependent cell-mediated cytotoxicity employing the novel anti-PD-L1 antibody avelumab. Oncotarget 7, 33498–33511 (2016).
pubmed: 27172898
pmcid: 5085098
doi: 10.18632/oncotarget.9256
Yates, A. D. et al. Ensembl 2020. Nucleic Acids Res. 48, D682–D688 (2020).
pubmed: 31691826
Li, H. & Durbin, R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25, 1754–1760 (2009).
pubmed: 19451168
pmcid: 2705234
doi: 10.1093/bioinformatics/btp324
Jones, S. J. et al. Evolution of an adenocarcinoma in response to selection by targeted kinase inhibitors. Genome Biol. 11, R82 (2010).
pubmed: 20696054
pmcid: 2945784
doi: 10.1186/gb-2010-11-8-r82
Ha, G. et al. Integrative analysis of genome-wide loss of heterozygosity and monoallelic expression at nucleotide resolution reveals disrupted pathways in triple-negative breast cancer. Genome Res. 22, 1995–2007 (2012).
pubmed: 22637570
pmcid: 3460194
doi: 10.1101/gr.137570.112
Li, H. et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics 25, 2078–2079 (2009).
pubmed: 19505943
pmcid: 2723002
doi: 10.1093/bioinformatics/btp352
Ding, J. et al. Feature-based classifiers for somatic mutation detection in tumour-normal paired sequencing data. Bioinformatics 28, 167–175 (2012).
pubmed: 22084253
doi: 10.1093/bioinformatics/btr629
Saunders, C. T. et al. Strelka: accurate somatic small-variant calling from sequenced tumor-normal sample pairs. Bioinformatics 28, 1811–1817 (2012).
pubmed: 22581179
doi: 10.1093/bioinformatics/bts271
Simpson, J. T. et al. ABySS: a parallel assembler for short read sequence data. Genome Res. 19, 1117–1123 (2009).
pubmed: 19251739
pmcid: 2694472
doi: 10.1101/gr.089532.108
Birol, I. et al. De novo transcriptome assembly with ABySS. Bioinformatics 25, 2872–2877 (2009).
pubmed: 19528083
doi: 10.1093/bioinformatics/btp367
Iyer, M. K., Chinnaiyan, A. M. & Maher, C. A. ChimeraScan: a tool for identifying chimeric transcription in sequencing data. Bioinformatics 27, 2903–2904 (2011).
pubmed: 21840877
pmcid: 3187648
doi: 10.1093/bioinformatics/btr467
McPherson, A. et al. deFuse: an algorithm for gene fusion discovery in tumor RNA-Seq data. PLoS Comput. Biol. 7, e1001138 (2011).
pubmed: 21625565
pmcid: 3098195
doi: 10.1371/journal.pcbi.1001138
Chen, X. et al. Manta: rapid detection of structural variants and indels for germline and cancer sequencing applications. Bioinformatics 32, 1220–1222 (2016).
pubmed: 26647377
doi: 10.1093/bioinformatics/btv710
Rausch, T. et al. DELLY: structural variant discovery by integrated paired-end and split-read analysis. Bioinformatics 28, i333–i339 (2012).
pubmed: 22962449
pmcid: 3436805
doi: 10.1093/bioinformatics/bts378
Reisle, C. et al. MAVIS: merging, annotation, validation, and illustration of structural variants. Bioinformatics 35, 515–517 (2019).
pubmed: 30016509
doi: 10.1093/bioinformatics/bty621
Cingolani, P. et al. A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3. Fly 6, 80–92 (2012).
pubmed: 22728672
pmcid: 3679285
doi: 10.4161/fly.19695
Butterfield, Y. S. et al. JAGuaR: junction alignments to genome for RNA-seq reads. PLoS ONE 9, e102398 (2014).
pubmed: 25062255
pmcid: 4111418
doi: 10.1371/journal.pone.0102398
Szolek, A. et al. OptiType: precision HLA typing from next-generation sequencing data. Bioinformatics 30, 3310–3316 (2014).
pubmed: 25143287
pmcid: 4441069
doi: 10.1093/bioinformatics/btu548
Jurtz, V. et al. NetMHCpan-4.0: improved peptide-MHC class I interaction predictions integrating eluted ligand and peptide binding affinity data. J. Immunol. 199, 3360–3368 (2017).
pubmed: 28978689
doi: 10.4049/jimmunol.1700893
Giudicelli, V., Chaume, D. & Lefranc, M.-P. IMGT/GENE-DB: a comprehensive database for human and mouse immunoglobulin and T cell receptor genes. Nucleic Acids Res. 33, D256–D261 (2005).
pubmed: 15608191
doi: 10.1093/nar/gki010
Cohen, C. J., Zhao, Y., Zheng, Z., Rosenberg, S. A. & Morgan, R. A. Enhanced antitumor activity of murine-human hybrid T-cell receptor (TCR) in human lymphocytes is associated with improved pairing and TCR/CD3 stability. Cancer Res. 66, 8878–8886 (2006).
pubmed: 16951205
pmcid: 2147082
doi: 10.1158/0008-5472.CAN-06-1450
Robinson, J., Halliwell, J. A., McWilliam, H., Lopez, R. & Marsh, S. G. E. IPD-the Immuno Polymorphism Database. Nucleic Acids Res. 41, D1234–D1240 (2013).
pubmed: 23180793
doi: 10.1093/nar/gks1140
Chen, Y. et al. Discovery of cross-reactive probes and polymorphic CpGs in the Illumina Infinium HumanMethylation450 microarray. Epigenetics 8, 203–209 (2013).
pubmed: 23314698
pmcid: 3592906
doi: 10.4161/epi.23470
Cancer Genome Atlas Research Network et al. Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. N. Engl. J. Med. 372, 2481–2498 (2015).
doi: 10.1056/NEJMoa1402121
Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature 513, 202–209 (2014).
doi: 10.1038/nature13480
Gaujoux, R. & Seoighe, C. A flexible R package for nonnegative matrix factorization. BMC Bioinforma. 11, 367 (2010).
doi: 10.1186/1471-2105-11-367
Ren, X. & Kuan, P. F. methylGSA: a Bioconductor package and Shiny app for DNA methylation data length bias adjustment in gene set testing. Bioinformatics 35, 1958–1959 (2019).
pubmed: 30346483
doi: 10.1093/bioinformatics/bty892
Johann, P. D. et al. Atypical teratoid/rhabdoid tumors are comprised of three epigenetic subgroups with distinct enhancer landscapes. Cancer Cell 29, 379–393 (2016).
pubmed: 26923874
doi: 10.1016/j.ccell.2016.02.001