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Evaluation of tumor-infiltrating lymphocytes in osteosarcomas of the jaws: a multicenter study

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Abstract

The aim of the present study was to investigate the profile of tumor-infiltrating lymphocytes (TIL) in osteosarcomas of the jaws (OSJ). A total of 21 OSJ samples were analyzed in a retrospective and cross-sectional multicenter study. Immunohistochemistry was performed to determine the recognition of TIL such as CD4+, CD8+, granzyme B+ (GrB), programmed cell death protein+ (PD-1), and cytotoxic T lymphocyte-associated antigen 4+ (CTLA-4) in intratumoral and peripheral (stromal) regions. Positivity was determined based on the percentage and density of TIL+ per square millimeter [1 = absent (< 25 cells/mm2), 2 = low (25 to 130 cells/mm2), and 3 = high (> 130 cells/mm2)]. The association of TIL density with clinicopathologic data was determined by the Mann-Whitney test (p < 0.05). OSJ were positive for CD8+ cells in 45% (n = 9) of cases, for CD4+ cells in 30% (n = 6) of cases, and for CTLA-4+ in 4.8% (n = 1) of cases, with a score of 2 (low TIL) in all cases. All cases were negative for GrB and PD-1 (score 1). No association was observed between immune infiltrate and clinicopathologic findings. OSJ showed a microenvironment with low TIL, including failure of effectiveness of the antitumor immune response (absence of GrB+ cells), and few cells exhibited immunotherapeutic targets, such as CTLA-4 and PD-1.

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References

  1. de Arruda JAA, Silva LVO, Kato CNAO, Schuch LF, Batista AC, Costa NL, Tarquinio SBC, Rivero ERC, Carrard VC, Martins MD, Sobral APV, Mesquita RA (2017) A multicenter study of malignant oral and maxillofacial lesions in children and adolescents. Oral Oncol 75:39–45

    Article  PubMed  Google Scholar 

  2. Paparella ML, Olvi LG, Brandizzi D, Keszler A, Santini-Araujo E, Cabrini RL (2013) Osteosarcoma of the jaw: an analysis of a series of 74 cases. Histopathology 63(4):551–557

    PubMed  Google Scholar 

  3. Chaudhary M, Chaudhary SD (2012) Osteosarcoma of jaws. J Oral Maxillofac Pathol 16(2):233–238

    Article  PubMed  PubMed Central  Google Scholar 

  4. Chen YM, Shen QC, Gokavarapu S, Ong HS, Cao W, Ji T (2016) Osteosarcoma of the mandible: a site-specific study on survival and prognostic factors. J Craniofac Surg 27(8):1929–1933

    Article  CAS  PubMed  Google Scholar 

  5. Asioli S, Righi A, Rucci P, Tarsitano A, Marchetti C, Bacchini P, Balbi T, Bertoni F, Foschini MP (2017) p16 protein expression and correlation with clinical and pathological features in osteosarcoma of the jaws: experience of 37 cases. Head Neck 39(9):1825–1831

    Article  PubMed  Google Scholar 

  6. Heymann MF, Lézot F, Heymann D (2017) The contribution of immune infiltrates and the local microenvironment in the pathogenesis of osteosarcoma. Cell Immunol

  7. Liu B, Huang Y, Sun Y, Zhang J, Yao Y, Shen Z, Xiang D, He A (2016) Prognostic value of inflammation-based scores in patients with osteosarcoma. Sci Rep 6:39862

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Liu T, Fang XC, Ding Z, Sun ZG, Sun LM, Wang YL (2015) Pre-operative lymphocyte-to-monocyte ratio as a predictor of overall survival in patients suffering from osteosarcoma. FEBS Open Bio 5:682–687

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Koirala P, Roth ME, Gill J, Piperdi S, Chinai JM, Geller DS, Hoang BH, Park A, Fremed MA, Zang X, Gorlick R (2016) Immune infiltration and PD-L1 expression in the tumor microenvironment are prognostic in osteosarcoma. Sci Rep 6:30093

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Fritzsching B, Fellenberg J, Moskovszky L, Sápi Z, Krenacs T, Machado I, Poeschl J, Lehner B, Szendrõi M, Bosch AL, Bernd L, Csóka M, Mechtersheimer G, Ewerbeck V, Kinscherf R, Kunz P (2015) CD8(+)/FOXP3(+)-ratio in osteosarcoma microenvironment separates survivors from non-survivors: a multicenter validated retrospective study. Oncoimmunology 4(3):e990800

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12(4):252–264

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ribas A, Wolchok JD (2018) Cancer immunotherapy using checkpoint blockade. Science 359(6382):1350–1355

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Schadendorf D, Hodi FS, Robert C, Weber JS, Margolin K, Hamid O, Patt D, Chen TT, Berman DM, Wolchok JD (2015) Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J Clin Oncol 33(17):1889–1894

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Zheng B, Ren T, Huang Y, Sun K, Wang S, Bao X, Liu K, Guo W (2018) PD-1 axis expression in musculoskeletal tumors and antitumor effect of nivolumab in osteosarcoma model of humanized mouse. J Hematol Oncol 11(1):16 Erratum in: J Hematol Oncol 2018;11(1):37

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. van Erp AEM, Versleijen-Jonkers YMH, Hillebrandt-Roeffen MHS, van Houdt L, Gorris MAJ, van Dam LS, Mentzel T, Weidema ME, Savci-Heijink CD, Desar IME, Merks HHM, van Noesel MM, Shipley J, van der Graaf WTA, Flucke UE, Meyer-Wentrup FAG (2017) Expression and clinical association of programmed cell death-1, programmed death-ligand-1 and CD8(+) lymphocytes in primary sarcomas is subtype dependent. Oncotarget 8(41):71371–71384

    PubMed  PubMed Central  Google Scholar 

  16. Gomez-Brouchet A, Illac C, Gilhodes J, Bouvier C, Aubert S, Guinebretiere JM, Marie B, Larousserie F, Entz-Werlé N, de Pinieux G, Filleron T, Minard V, Minville V, Mascard E, Gouin F, Jimenez M, Ledeley MC, Piperno-Neumann S, Brugieres L, Rédini F (2017) CD163-positive tumor-associated macrophages and CD8-positive cytotoxic lymphocytes are powerful diagnostic markers for the therapeutic stratification of osteosarcoma patients: an immunohistochemical analysis of the biopsies fromthe French OS2006 phase 3 trial. Oncoimmunology 6(9):e1331193

    Article  PubMed  PubMed Central  Google Scholar 

  17. Saraf AJ, Fenger JM, Roberts RD (2018) Osteosarcoma: accelerating progress makes for a hopeful future. Front Oncol 8:4

    Article  PubMed  PubMed Central  Google Scholar 

  18. Costa Arantes DA, Gonçalves AS, Jham BC, Duarte ECB, de Paula ÉC, de Paula HM, Mendonça EF, Batista AC (2017) Evaluation of HLA-G, HLA-E, and PD-L1 proteins in oral osteosarcomas. Oral Surg Oral Med Oral Pathol Oral Radiol 123(6):188–196

    Article  Google Scholar 

  19. El-Naggar AK, Chan JKC, Grandis JR, Takata T, Slootweg PJ (2017) World Health Organization classification of head and neck tumours. IARC Press, Lyon

    Google Scholar 

  20. Teng MW, Ngiow SF, Ribas A, Smyth MJ (2015) Classifying cancers based on T-cell infiltration and PD-L1. Cancer Res 75(11):2139–2145

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Webb JR, Milne K, Kroeger DR, Nelson BH (2016) PD-L1 expression is associated with tumor-infiltrating T cells and favorable prognosis in high-grade serous ovarian cancer. Gynecol Oncol 141(2):293–302

    Article  CAS  PubMed  Google Scholar 

  22. Sundara YT, Kostine M, Cleven AH, Bovée JV, Schilham MW, Cleton-Jansen AM (2017) 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. Cancer Immunol Immunother 66(1):119–128

    Article  CAS  PubMed  Google Scholar 

  23. Palmerini E, Agostinelli C, Picci P, Pileri S, Marafioti T, Lollini PL, Scotlandi K, Longhi A, Benassi MS, Ferrari S (2017) Tumoral immune-infiltrate (IF), PD-L1 expression and role of CD8/TIA-1 lymphocytes in localized osteosarcoma patients treated within protocol ISG-OS1. Oncotarget 8(67):111836–111846

    Article  PubMed  PubMed Central  Google Scholar 

  24. Ratti C, Botti L, Cancila V, Galvan S, Torselli I, Garofalo C, Manara MC, Bongiovanni L, Valenti CF, Burocchi A, Parenza M, Cappetti B, Sangaletti S, Tripodo C, Scotlandi K, Colombo MP, Chiodoni C (2017) Trabectedin overrides osteosarcoma differentiative block and reprograms the tumor immune environment enabling effective combination with immune checkpoint inhibitors. Clin Cancer Res 23(17):5149–5161

    Article  CAS  PubMed  Google Scholar 

  25. Takahashi Y, Yasui T, Tamari K, Minami K, Otani K, Isohashi F, Seo Y, Kambe R, Koizumi M, Ogawa K (2017) Radiation enhanced the local and distant anti-tumor efficacy in dual immune checkpoint blockade therapy in osteosarcoma. PLoS One 12(12):e0189697

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lussier DM, Johnson JL, Hingorani P, Blattman JN (2015) Combination immunotherapy with α-CTLA-4 and α-PD-L1 antibody blockade prevents immune escape and leads to complete control of metastatic osteosarcoma. J Immunother Cancer 3:21

    Article  PubMed  PubMed Central  Google Scholar 

  27. Lussier DM, O'Neill L, Nieves LM, McAfee MS, Holechek SA, Collins AW, Dickman P, Jacobsen J, Hingorani P, Blattman JN (2015) Enhanced T-cell immunity to osteosarcoma through antibody blockade of PD-1/PD-L1 interactions. J Immunother 38(3):96–106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Burgess M, Gorantla V, Weiss K, Tawbi H (2015) Immunotherapy in sarcoma: future horizons. Curr Oncol Rep 17(11):52

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank the Coordination for the Improvement of Higher Education Personnel (CAPES), the Brazilian National Council for Scientific and Technological Development (CNPq), and the Foundation for Research Support in the State of Goiás (FAPEG). ACB, RAM, EFM, and CFWN are research fellows at CNPq. The authors thank the Coordination for the Improvement of Higher Education Personnel (CAPES). JAAA and SFSC are the recipients of fellowships. Mrs. E. Greene provided English editing of the manuscript.

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Authors and Affiliations

  1. Department of Dentistry, School of Dentistry, Universidade Estadual da Paraíba, Campina Grande, PB, Brazil

    Pollianna Muniz Alves & Cassiano Francisco Weege Nonaka

  2. Department of Stomatology (Oral Pathology), School of Dentistry, Universidade Federal de Goiás, Goiânia, GO, Brazil

    Pollianna Muniz Alves, Diego Antônio Costa Arantes, Elismauro Francisco Mendonça & Aline Carvalho Batista

  3. Department of Oral Surgery and Pathology, School of Dentistry, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil

    José Alcides Almeida de Arruda, Sara Ferreira Santos Costa, Felipe Paiva Fonseca & Ricardo Alves Mesquita

  4. Service of Oral Pathology, Hospital Universitário João de Barros Barreto, Universidade Federal do Pará, Belém, PA, Brazil

    Lucas Lacerda Souza & Hélder Antônio Rebelo Pontes

  5. Departamento de Estomatologia (Patologia Oral), Faculdade de Odontologia, Universidade Federal de Goiás, Praça Universitária, S/N, Setor Universitário, Goiânia, GO, CEP 74605-220, Brazil

    Aline Carvalho Batista

Authors
  1. Pollianna Muniz Alves
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  2. José Alcides Almeida de Arruda
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  3. Diego Antônio Costa Arantes
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  5. Lucas Lacerda Souza
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  6. Hélder Antônio Rebelo Pontes
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  7. Felipe Paiva Fonseca
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  8. Ricardo Alves Mesquita
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  9. Cassiano Francisco Weege Nonaka
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  10. Elismauro Francisco Mendonça
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  11. Aline Carvalho Batista
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Contributions

PMA, DACA, LLS, SFSC, and JAAA conducted a literature review, organized the data of the clinical cases, and conducted the immunohistochemical reactions, and morphological and immunohistochemical analysis of samples. HARP, RAM, CFWN, and EFM contributed cases from their services, and reviewed and classified, morphologically, all cases. ACB, PMA, and JAAA contributed to the design of the work. FPF was responsible for data interpretation. ACB, PMA, RAM, and HARP contributed to the conception of the work. All authors gave final approval for publication.

Corresponding author

Correspondence to Aline Carvalho Batista.

Ethics declarations

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Conflict of interest

All authors declare that they have no conflict of interest.

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Alves, P.M., de Arruda, J.A.A., Arantes, D.A.C. et al. Evaluation of tumor-infiltrating lymphocytes in osteosarcomas of the jaws: a multicenter study. Virchows Arch 474, 201–207 (2019). https://doi.org/10.1007/s00428-018-2499-6

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  • DOI: https://doi.org/10.1007/s00428-018-2499-6

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