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Cited by 111Cancer Immunotherapy and BiomarkersSarcoma Diagnosis and TreatmentImmunotherapy and Immune Responses

Increased PD-L1 and T-cell infiltration in the presence of HLA class I expression in metastatic high-grade osteosarcoma: a rationale for T-cell-based immunotherapy

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Sundara, Yayan T., Kostine, Marie, Cleven, Arjen H. G., Bovée, Judith V. M. G., Schilham, Marco W., Cleton-Jansen, Anne-Marie·2017·Cancer Immunology, Immunotherapy
DOI 10.1007/s00262-016-1925-3PMC PMC5222929
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Abstract

INTRODUCTION: Immunotherapy may be an excellent choice for treating osteosarcoma given its exceptionally high genomic instability, potentially generating neoantigens. In this study, we aim to investigate the HLA class I expression, PD-L1 and tumour-infiltrating lymphocytes in primary osteosarcomas and relapses/metastases, as well as their changes during disease progression. MATERIALS AND METHODS: Tumour samples from multiple stages of the disease (pretreatment biopsies, surgical resections of primary osteosarcomas, relapses and metastases) were collected and stained for HLA-A (HCA2), HLA-B/C (HC10), β2-microglobulin and PD-L1 using immunohistochemistry on whole sections. Density and type of T-cell infiltrate were characterised by a triple immunofluorescent staining CD3-CD8-FOXP3. RESULTS: Overall, 85 formalin-fixed, paraffin-embedded blocks from 25 osteosarcoma patients were included. HLA class I expression was detected in 94% of osteosarcomas (strongly positive in 56%, heterogeneous in 38%) and negative or weakly positive in 6%, without differences between the stages of the disease. HLA-A expression was more frequently negative than HLA-B/C. Tumour-infiltrating lymphocytes were highly heterogeneous and mainly observed in tumour areas with expression of HLA class I. Density of T cells was significantly higher in metastases than in primary tumours and local relapses (p = 0.0003). Positive PD-L1 expression was found in 13% of primary tumours, 25% of relapses and 48% of metastases and correlated with a high T-cell infiltrate (p = 0.002). CONCLUSION: An increased number of tumour-infiltrating T cells and PD-L1 expression in metastases compared with primary tumours, suggesting accessibility for T cells, could imply that osteosarcoma patients with metastatic disease may benefit from T-cell-based immunotherapy.

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  • Osteosarcoma has variable PD-L1 expression and frequent deletions of MHC class I, which may promote immune evasion.

    “Osteosarcoma has been shown to have variable PD-L1 expression and frequent deletions of MHC class I, which may promote immune evasion [56].”

    From Advances on immunotherapy for osteosarcoma (2024) · cites this paper as [56]

    The Results report variable PD-L1 expression across primary tumours, relapses and metastases. They also report heterogeneous HLA class I expression, and the Discussion describes loss or down-regulation as a possible means of immune escape. But the paper does not establish frequent MHC class I deletions: it measured expression, and only 6% of evaluated tumours were negative or weakly positive for HLA class I. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • An increased number of tumour-infiltrating T cells and PD-L1 expression in metastases compared with primary tumours suggests accessibility for T cells, and could imply that osteosarcoma patients with metastatic disease may benefit from T-cell-based immunotherapy.

    “An increased number of tumour-infiltrating T cells and PD-L1 expression in metastases compared with primary tumours, suggesting accessibility for T cells, could imply that osteosarcoma patients with metastatic disease may benefit from T-cell-based immunotherapy [56].”

    From Advances on immunotherapy for osteosarcoma (2024) · cites this paper as [56]

  • In osteosarcoma, the number of T cells in metastatic lesions is significantly higher than that in primary and recurrent lesions in situ.

    “In osteosarcoma, the number of T cells in metastatic lesions is significantly higher than that in primary and recurrent lesions in situ [56].”

    From Advances on immunotherapy for osteosarcoma (2024) · cites this paper as [56]

  • Metastatic osteosarcoma express higher PD-L1 than primary tumors.

    “Metastatic osteosarcoma express higher PD-L1 than primary tumors.”

    From Advances on immunotherapy for osteosarcoma (2024) · cites this paper as [56]

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Research works printed but not linked: 29

  1. [1]Rosenberg A Cleton-Jansen A de Pinieux G Fletcher CDM Bridge JA Hogendoorn PC Mertens F Conventional osteosarcoma WHO classification of tumours of soft tissue and bone 2013 4 Lyon IARC Press 282 288
  2. [2]The ESMO/European Sarcoma Network Working Group Bone sarcomas: ESMO clinical practice guidelines for diagnosis, treatment and follow-up Ann Oncol 2014 25 Suppl 3 113 123 10.1093/annonc/mdu256 25210081 · DOI
  3. [3]Kansara M Teng MW Smyth MJ Thomas DM Translational biology of osteosarcoma Nat Rev Cancer 2014 14 722 735 10.1038/nrc3838 25319867 · DOI · Paper page
  4. [4]Botter SM Neri D Fuchs B Recent advances in osteosarcoma Curr Opin Pharmacol 2014 16 15 23 10.1016/j.coph.2014.02.002 24632219 · DOI
  5. [5]Lorenz S Barøy T Sun J Nome T Vodák D Bryne J-C Unscrambling the genomic chaos of osteosarcoma reveals extensive transcript fusion, recurrent rearrangements and frequent novel TP53 aberrations Oncotarget 2016 7 5273 5288 26672768 PMC4868685
  6. [7]Lim J Poulin NM Nielsen TO New strategies in sarcoma: linking genomic and immunotherapy approaches to molecular subtype Clin Cancer Res 2015 21 4753 4759 10.1158/1078-0432.CCR-15-0831 26330427 · DOI
  7. [8]Coley WB II Contribution to the knowledge of sarcoma Ann Surg 1891 14 199 220 10.1097/00000658-189112000-00015 17859590 PMC1428624 · DOI
  8. [9]Cleton-Jansen A-M Buddingh EP Lankester AC Immunotherapy: is it different for sarcomas? Oncoimmunology 2012 1 255 257 10.4161/onci.1.2.18345 22720262 PMC3376989 · DOI
  9. [10]Tumeh PC Harview CL Yearley JH Shintaku IP Taylor EJM Robert L PD-1 blockade induces responses by inhibiting adaptive immune resistance Nature 2014 515 568 571 10.1038/nature13954 25428505 PMC4246418 · DOI · Paper page
  10. [11]Thor Straten P Garrido F Targetless T cells in cancer immunotherapy J Immunother Cancer. 2016 4 23 10.1186/s40425-016-0127-z 27096099 PMC4835921 · DOI
  11. [12]Pardoll DM The blockade of immune checkpoints in cancer immunotherapy Nat Rev Cancer 2012 12 252 264 10.1038/nrc3239 22437870 PMC4856023 · DOI · Paper page
  12. [13]Kostine M Cleven AH de Miranda NFCC Italiano A Cleton-Jansen A-M Bovée JVMG Analysis of PD-L1, T-cell infiltrate and HLA expression in chondrosarcoma indicates potential for response to immunotherapy specifically in the dedifferentiated subtype Mod Pathol 2016 27312065
  13. [14]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 2018 2028 10.1056/NEJMoa1501824 25891174 · DOI · Paper page
  14. [15]Punt S van Vliet ME Spaans VM de Kroon CD Fleuren GJ Gorter A FoxP3(+) and IL-17(+) cells are correlated with improved prognosis in cervical adenocarcinoma Cancer Immunol Immunother 2015 64 745 753 10.1007/s00262-015-1678-4 25795131 PMC4456995 · DOI
  15. [16]Nada OH Ahmed NS Abou Gabal HH Prognostic significance of HLA EMR8-5 immunohistochemically analyzed expression in osteosarcoma Diagn Pathol. 2014 9 72 10.1186/1746-1596-9-72 24667142 PMC3987053 · DOI
  16. [17]Tsukahara T Kawaguchi S Torigoe T Asanuma H Nakazawa E Shimozawa K Prognostic significance of HLA class I expression in osteosarcoma defined by anti-pan HLA class I monoclonal antibody, EMR8-5 Cancer Sci 2006 97 1374 1380 10.1111/j.1349-7006.2006.00317.x 16995877 PMC11158095 · DOI · Paper page
  17. [18]Al-Batran S-E Rafiyan M-R Atmaca A Neumann A Karbach J Bender A Intratumoral T-cell infiltrates and MHC class I expression in patients with stage IV melanoma Cancer Res 2005 65 3937 3941 10.1158/0008-5472.CAN-04-4621 15867394 · DOI
  18. [19]Turcotte S Katz SC Shia J Jarnagin WR Kingham TP Allen PJ Tumor MHC class I expression improves the prognostic value of T-cell density in resected colorectal liver metastases Cancer Immunol Res. 2014 2 530 537 10.1158/2326-6066.CIR-13-0180 24894090 PMC4048875 · DOI
  19. [20]Théoleyre S Mori K Cherrier B Passuti N Gouin F Rédini F Phenotypic and functional analysis of lymphocytes infiltrating osteolytic tumors: use as a possible therapeutic approach of osteosarcoma BMC Cancer 2005 5 123 10.1186/1471-2407-5-123 16188028 PMC1262697 · DOI
  20. [21]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 6 202 216 10.1158/2159-8290.CD-15-0283 26645196 PMC4744499 · DOI · Paper page
  21. [22]Moriarity BS Otto GM Rahrmann EP Rathe SK Wolf NK Weg MT A sleeping beauty forward genetic screen identifies new genes and pathways driving osteosarcoma development and metastasis Nat Genet 2015 47 615 624 10.1038/ng.3293 25961939 PMC4767150 · DOI
  22. [23]Lussier DM O’Neill L Nieves LM McAfee MS Holechek SA Collins AW Enhanced T-cell immunity to osteosarcoma through antibody blockade of PD-1/PD-L1 interactions J Immunother 2015 38 96 106 10.1097/CJI.0000000000000065 25751499 PMC6426450 · DOI · Paper page
  23. [24]Shen JK Cote GM Choy E Yang P Harmon D Schwab J Programmed cell death ligand 1 expression in osteosarcoma Cancer Immunol Res. 2014 2 690 698 10.1158/2326-6066.CIR-13-0224 24866169 PMC4082476 · DOI
  24. [25]Zheng W Xiao H Liu H Zhou Y Expression of programmed death 1 is correlated with progression of osteosarcoma APMIS 2015 123 102 107 10.1111/apm.12311 25257510 · DOI
  25. [27]Seliger B Cabrera T Garrido F Ferrone S HLA class I antigen abnormalities and immune escape by malignant cells Semin Cancer Biol 2002 1 3 13 10.1006/scbi.2001.0404 11926409 · DOI
  26. [28]Seliger B Molecular mechanisms of MHC class I abnormalities and APM components in human tumors Cancer Immunol Immunother 2008 11 1719 1726 10.1007/s00262-008-0515-4 PMC11030176 18408926 · DOI
  27. [29]Dierssen JW de Miranda NF Ferrone S van Puijenbroek M Cornelisse CJ Fleuren GJ HNPCC versus sporadic microsatellite-unstable colon cancers follow different routes toward loss of HLA class I expression BMC Cancer 2007 22 7 33 PMC1808468 17316446
  28. [30]Schreiber RD Old LJ Smyth MJ Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion Science 2011 331 1565 1570 10.1126/science.1203486 21436444 · DOI · Paper page
  29. [31]Fernández L Valentín J Zalacain M Leung W Patiño-Garcia A Pérez-Martínez A Activated and expanded natural killer cells target osteosarcoma tumor initiating cells in an NKG2D-NKG2DL dependent manner Cancer Lett 2015 1 54 63 10.1016/j.canlet.2015.07.042 26276724 · DOI

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Sorted by citations

Authors
Sundara, Y. T., Kostine, M., Cleven, A. H. G., Bovée, J. V. M. G., Schilham, M. W., & Cleton-Jansen, A.-M.
Affiliations
Leiden University Medical Center (NL)
Corresponding author
Cleton-Jansen, Anne-Marie
ORCID
Venue
Cancer Immunology, Immunotherapy
Publisher
Springer Science and Business Media LLC
Published
2016-11-16
Volume
66
Issue
1
Pages
119-128
ISSN
  • 0340-7004 (ISSN-L)
  • 1432-0851
DOI
10.1007/s00262-016-1925-3
PMC
PMC5222929
OpenAlex
W2553835169
Cited by
111
References
3
Citations by year
2026: 5 · 2025: 8 · 2024: 7 · 2023: 10 · 2022: 9 · 2021: 13 · 2020: 24 · 2019: 12 · 2018: 12 · 2017: 11
FWCI
6.29
Type
journal article
Language
en
Open access
Licence
Locations
  • Cancer Immunology Immunotherapy (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Leiden Repository (Leiden University) (submittedVersion, cc-by)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
  • Leiden Repository (Leiden University) (submittedVersion)
Funders
EuroSARC (278742)
Topics
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Sarcoma Diagnosis and Treatment
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords
osteosarcoma, PD-L1, HLA class I expression, tumor-infiltrating lymphocytes, metastasis, T cell-based immunotherapy, HLA-A, CD8+ T cells, Foxp3, disease progression, tumor immunology
MeSH terms
Adolescent, Adult, Aged, Bone Neoplasms, Child, Female, Humans, Immunotherapy, Male, Middle Aged, Neoplasm Metastasis, Prognosis, Osteosarcoma, Biomarkers, Tumor, Histocompatibility Antigens Class I, Lymphocytes, Tumor-Infiltrating, Young Adult, B7-H1 Antigen

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