Top

Journal of Cancer Research and Clinical Oncology

Published in:

01-10-2020 | osteosarcoma | Original Article – Clinical Oncology

PD-L1 and IDO1 expression and tumor-infiltrating lymphocytes in osteosarcoma patients: comparative study of primary and metastatic lesions

Authors: Yu Toda, Kenichi Kohashi, Yuichi Yamada, Masato Yoshimoto, Shin Ishihara, Yoshihiro Ito, Takeshi Iwasaki, Hidetaka Yamamoto, Yoshihiro Matsumoto, Yasuharu Nakashima, Masaaki Mawatari, Yoshinao Oda

Published in: Journal of Cancer Research and Clinical Oncology | Issue 10/2020

Abstract

Purpose

Programmed death ligand 1 (PD-L1) and indoleamine 2,3-dioxygenase 1 (IDO1) are immunosuppressive proteins known to be associated with poor prognosis in various cancers. However, their expression and clinical relevance in osteosarcoma remain unknown. In this study, the relationships of PD-L1 and IDO1 expression with clinicopathological features and prognosis were explored.

Methods

The expression of PD-L1, IDO1, CD3, CD4, and CD8 in 112 formalin-fixed, paraffin-embedded tumor tissues collected by biopsy or surgical resection from 56 osteosarcoma patients was evaluated immunohistochemically. Moreover, four osteosarcoma cell lines were evaluated for the effects of IFNγ on PD-L1 and IDO1 mRNA expression by real-time reverse-transcription polymerase chain reaction.

Results

In pre-neoadjuvant chemotherapy (NAC) primary specimens, 10 cases (17%) showed PD-L1 expression and 12 (21%) showed IDO1 expression. Six of ten cases (60%) with PD-L1 positivity co-expressed IDO1. In post-NAC metastatic lesions, the frequency of immunoexpression of PD-L1 and IDO1 was increased compared with that in pre-NAC specimens. PD-L1 and/or IDO1 expression was not associated with poor prognosis. PD-L1 immunoexpression was significantly associated with the infiltration of CD3⁺ T cells, CD4⁺ T cells, and CD8⁺ T cells; while, IDO1 immunoexpression was significantly associated with the infiltration of CD3⁺ T cells and CD4⁺ T cells. In all osteosarcoma cell lines, PD-L1 and IDO1 expression was upregulated by stimulation with IFNγ.

Conclusion

Our results suggest that the PD-L1 and IDO1 immune checkpoint inhibitors may provide clinical benefit in osteosarcoma patients with metastatic lesions after conventional chemotherapy.

Available only for authorised users

Abiko K, Mandai M, Hamanishi J et al (2013) PD-L1 on tumor cells is induced in ascites and promotes peritoneal dissemination of ovarian cancer through CTL dysfunction. Clin Cancer Res 19:1363–1374. https://doi.org/10.1158/1078-0432.CCR-12-2199CrossRefPubMed

Abiko K, Matsumura N, Hamanishi J et al (2015) IFN-gamma from lymphocytes induces PD-L1 expression and promotes progression of ovarian cancer. Br J Cancer 112:1501–1509. https://doi.org/10.1038/bjc.2015.101CrossRefPubMedPubMedCentral

Angela Y, Haferkamp S, Weishaupt C et al (2019) Combination of denosumab and immune checkpoint inhibition: experience in 29 patients with metastatic melanoma and bone metastases. Cancer Immunol Immunother 68:1187–1194. https://doi.org/10.1007/s00262-019-02353-5CrossRefPubMed

Dunn GP, Koebel CM, Schreiber RD (2006) Interferons, immunity and cancer immunoediting. Nat Rev Immunol 2006:836–848CrossRef

Castro F, Cardoso AP, Gonçalves RM, Serre K, Oliveira MJ (2018) Interferon-gamma at the crossroads of tumor immune surveillance or evasion. Front Immunol 9:847. https://doi.org/10.3389/fimmu.2018.00847CrossRefPubMedPubMedCentral

Deng C, Li Z, Guo S et al (2017) Tumor PD-L1 expression is correlated with increased TILs and poor prognosis in penile squamous cell carcinoma. Oncoimmunology 6:e1269047. https://doi.org/10.1080/2162402X.2016.1269047CrossRefPubMed

Fournel L, Wu Z, Stadler N et al (2019) Cisplatin increases PD-L1 expression and optimizes immune check-point blockade in non-small cell lung cancer. Cancer Lett 464:5–14. https://doi.org/10.1016/j.canlet.2019.08.005CrossRefPubMed

Gao F, Zhang C, Qiu WX et al (2018) PD-1 blockade for improving the antitumor efficiency of polymer-doxorubicin nanoprodrug. Small 14:e1802403. https://doi.org/10.1002/smll.201802403CrossRefPubMed

Gill D, Hahn AW, Sonpavde G, Agarwal N (2016) Immunotherapy of advanced renal cell carcinoma: current and future therapies. Hum Vaccin Immunother 12:2997–3004. https://doi.org/10.1080/21645515.2016.1212794CrossRefPubMedPubMedCentral

Gu L, Chen M, Guo D et al (2017) PD-L1 and gastric cancer prognosis: a systematic review and meta-analysis. PLoS ONE 12:e0182692. https://doi.org/10.1371/journal.pone.0182692CrossRefPubMedPubMedCentral

Harrison DJ, Schwartz CL (2017) Osteogenic sarcoma: systemic chemotherapy options for localized disease. Curr Treat Options Oncol 18:24. https://doi.org/10.1007/s11864-017-0464-2CrossRefPubMed

Iwamoto Y, Tanaka K, Isu K et al (2009) Multiinstitutional phase II study of neoadjuvant chemotherapy for osteosarcoma (NECO study) in Japan: NECO-93J and NECO-95J. J Orthop Sci 14:397–404. https://doi.org/10.1007/s00776-009-1347-6CrossRefPubMed

Jie HB, Srivastava RM, Argiris A, Bauman JE, Kane LP, Ferris RL (2017) Increased PD-1(+) and TIM-3(+) TILs during cetuximab therapy inversely correlate with response in head and neck cancer patients. Cancer Immunol Res 5:408–416. https://doi.org/10.1158/2326-6066.CIR-16-0333CrossRefPubMedPubMedCentral

Jung HI, Jeong D, Ji S, Ahn TS et al (2017) Overexpression of PD-L1 and PD-L2 is associated with poor prognosis in patients with hepatocellular carcinoma. Cancer Res Treat 49:246–254. https://doi.org/10.4143/crt.2016.066CrossRefPubMed

Kim HS, Kim JY, Lee YJ et al (2018) Expression of programmed cell death ligand 1 and immune checkpoint markers in residual tumors after neoadjuvant chemotherapy for advanced high-grade serous ovarian cancer. Gynecol Oncol 151:414–421. https://doi.org/10.1016/j.ygyno.2018.08.023CrossRefPubMed

Kiyozumi Y, Baba Y, Okadome K et al (2019) IDO1 expression is associated with immune tolerance and poor prognosis in patients with surgically resected esophageal cancer. Ann Surg 269:1101–1108. https://doi.org/10.1097/SLA.0000000000002754CrossRefPubMed

Koirala P, Roth ME, Gill J et al (2016) Immune infiltration and PD-L1 expression in the tumor microenvironment are prognostic in osteosarcoma. Sci Rep 6:30093. https://doi.org/10.1038/srep30093CrossRefPubMedPubMedCentral

Kozuma Y, Takada K, Toyokawa G et al (2018) Indoleamine 2,3-dioxygenase 1 and programmed cell death-ligand 1 co-expression correlates with aggressive features in lung adenocarcinoma. Eur J Cancer 101:20–29. https://doi.org/10.1016/j.ejca.2018.06.020CrossRefPubMed

Liao Y, Chen L, Feng Y et al (2017) Targeting programmed cell death ligand 1 by CRISPR Cas9 in osteosarcoma cells. Oncotarget 8:30276–30287. https://doi.org/10.18632/oncotarget.16326CrossRefPubMedPubMedCentral

Lin YM, Sung WW, Hsieh M et al (2015) High PD-L1 expression correlates with metastasis and poor prognosis in oral squamous cell carcinoma. PLoS ONE 10:e0142656. https://doi.org/10.1371/journal.pone.0142656CrossRefPubMedPubMedCentral

Lo CS, Sanii S, Kroeger DR et al (2017) Neoadjuvant chemotherapy of ovarian cancer results in three patterns of tumor-infiltrating lymphocyte response with distinct implications for immunotherapy. Clin Cancer Res 23:925–934. https://doi.org/10.1158/1078-0432.CCR-16-1433CrossRefPubMed

Ma WJ, Wang X, Yan WT et al (2018) Indoleamine-2,3-dioxygenase 1/cyclooxygenase 2 expression prediction for adverse prognosis in colorectal cancer. World J Gastroenterol 24:2181–2190. https://doi.org/10.3748/wjg.v24.i20.2181CrossRefPubMedPubMedCentral

Mandai M, Hamanishi J, Abiko K, Matsumura N, Baba T, Konishi I (2016) Dual faces of IFNgamma in cancer progression: a role of PD-L1 induction in the determination of pro- and antitumor immunity. Clin Cancer Res 22:2329–2334. https://doi.org/10.1158/1078-0432.CCR-16-0224CrossRefPubMed

Meng Y, Liang H, Hu J et al (2018) PD-L1 expression correlates with tumor infiltrating lymphocytes and response to neoadjuvant chemotherapy in cervical cancer. J Cancer 9:2938–2945. https://doi.org/10.7150/jca.22532CrossRefPubMedPubMedCentral

Mesnage SJL, Auguste A, Genistie C et al (2017) Neoadjuvant chemotherapy (NACT) increases immune infiltration and programmed death-ligand 1 (PD-L1) expression in epithelial ovarian cancer (EOC). Ann Oncol 28:651–657. https://doi.org/10.1093/annonc/mdw625CrossRefPubMed

Miyoshi H, Kiyasu J, Kato T et al (2016) PD-L1 expression on neoplastic or stromal cells is respectively a poor or good prognostic factor for adult T-cell leukemia/lymphoma. Blood 128:1374–1381. https://doi.org/10.1182/blood-2016-02-698936CrossRefPubMed

Muenst S, Schaerli AR, Gao F et al (2014) Expression of programmed death ligand 1 (PD-L1) is associated with poor prognosis in human breast cancer. Breast Cancer Res Treat 146:15–24. https://doi.org/10.1007/s10549-014-2988-5CrossRefPubMedPubMedCentral

Nakanishi J, Wada Y, Matsumoto K, Azuma M, Kikuchi K, Ueda S (2007) Overexpression of B7–H1 (PD-L1) significantly associates with tumor grade and postoperative prognosis in human urothelial cancers. Cancer Immunol Immunother 56:1173–1182. https://doi.org/10.1007/s00262-006-0266-zCrossRefPubMed

Negri GL, Grande BM, Delaidelli A et al (2019) Integrative genomic analysis of matched primary and metastatic pediatric osteosarcoma. J Pathol 249:319–331. https://doi.org/10.1002/path.5319CrossRefPubMed

Okita R, Maeda A, Shimizu K, Nojima Y, Saisho S, Nakata M (2017) PD-L1 overexpression is partially regulated by EGFR/HER2 signaling and associated with poor prognosis in patients with non-small-cell lung cancer. Cancer Immunol Immunother 66:865–876. https://doi.org/10.1007/s00262-017-1986-yCrossRefPubMed

Palmerini EAC, Picci P, Pileri S, Marafioti T, Lollini PL, Scotlandi K et al (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 8:111836–111846. https://doi.org/10.18632/oncotarget.22912CrossRefPubMedPubMedCentral

Parra ER, Villalobos P, Zhang J et al (2018) Immunohistochemical and image analysis-based study shows that several immune checkpoints are co-expressed in non-small cell lung carcinoma tumors. J Thorac Oncol 13:779–791. https://doi.org/10.1016/j.jtho.2018.03.002CrossRefPubMed

Pelekanou V, Carvajal-Hausdorf DE, Altan M et al (2017) Effect of neoadjuvant chemotherapy on tumor-infiltrating lymphocytes and PD-L1 expression in breast cancer and its clinical significance. Breast Cancer Res 19:91. https://doi.org/10.1186/s13058-017-0884-8CrossRefPubMedPubMedCentral

Perea F, Bernal M, Sanchez-Palencia A et al (2017) The absence of HLA class I expression in non-small cell lung cancer correlates with the tumor tissue structure and the pattern of T cell infiltration. Int J Cancer 140:888–899. https://doi.org/10.1002/ijc.30489CrossRefPubMed

Rosenbaum MW, Gigliotti BJ, Pai SI et al (2018) PD-L1 and IDO1 are expressed in poorly differentiated thyroid carcinoma. Endocr Pathol 29:59–67. https://doi.org/10.1007/s12022-018-9514-yCrossRefPubMedPubMedCentral

Schalper KA, Carvajal-Hausdorf D, McLaughlin J et al (2017) Differential expression and significance of PD-L1, IDO-1, and B7–H4 in human lung. Cancer Clin Cancer Res 23:370–378. https://doi.org/10.1158/1078-0432.CCR-16-0150CrossRefPubMed

Seeber A, Klinglmair G, Fritz J et al (2018) High IDO-1 expression in tumor endothelial cells is associated with response to immunotherapy in metastatic renal cell carcinoma. Cancer Sci 109:1583–1591. https://doi.org/10.1111/cas.13560CrossRefPubMedPubMedCentral

Sharma P, Retz M, Siefker-Radtke A et al (2017) Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol 18:312–322. https://doi.org/10.1016/S1470-2045(17),30065-7CrossRefPubMed

Shen JK, Cote GM, Choy E et al (2014) Programmed cell death ligand 1 expression in osteosarcoma. Cancer Immunol Res 2:690–698. https://doi.org/10.1158/2326-6066.CIR-13-0224CrossRefPubMedPubMedCentral

Shimizu T, Fuchimoto Y, Fukuda K, Okita H, Kitagawa Y, Kuroda T (2017) The effect of immune checkpoint inhibitors on lung metastases of osteosarcoma. J Pediatr Surg 52:2047–2050. https://doi.org/10.1016/j.jpedsurg.2017.08.030CrossRefPubMed

Sundara YT, Kostine M, Cleven AH, Bovee 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 66:119–128. https://doi.org/10.1007/s00262-016-1925-3CrossRefPubMed

Takamori S, Takada K, Tagawa T et al (2018) Differences in PD-L1 expression on tumor and immune cells between lung metastases and corresponding primary tumors. Surg Oncol 27:637–641. https://doi.org/10.1016/j.suronc.2018.08.001CrossRefPubMed

Tawbi HA, Burgess M, Bolejack V et al (2017) Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): a multicentre, two-cohort, single-arm, open-label, phase 2 trail. Lancet Oncol 18:1493–1501. https://doi.org/10.1016/S1470-2045(17),30624-1CrossRefPubMed

Torabi A, Amaya CN, Wians FH Jr, Bryan BA (2017) PD-1 and PD-L1 expression in bone and soft tissue sarcomas. Pathology 49:506–513. https://doi.org/10.1016/j.pathol.2017.05.003CrossRefPubMed

Troiano G, Caponio VCA, Zhurakivska K, Arena C et al (2018) High PD-L1 expression in the tumour cells did not correlate with poor prognosis of patients suffering for oral squamous cells carcinoma: a meta-analysis of the literature. Cell Prolif. https://doi.org/10.1111/cpr.12537CrossRefPubMedPubMedCentral

Uyttenhove C, Pilotte L, Theate IS et al (2003) Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat Med 9:1269–1274. https://doi.org/10.1038/nm934CrossRefPubMed

Wang Q, Liu F, Liu L (2017) Prognostic significance of PD-L1 in solid tumor: an updated meta-analysis. Medicine (Baltimore) 96:e6369. https://doi.org/10.1097/MD.0000000000006369CrossRef

Wang D, Niu X, Wang Z et al (2019) Multiregion sequencing reveals the genetic heterogeneity and evolutionary history of osteosarcoma and matched pulmonary metastases. Cancer Res 79:7–20. https://doi.org/10.1158/0008-5472.CAN-18-1086CrossRefPubMed

Yagi T, Baba Y, Ishimoto T et al (2019) PD-L1 expression, tumor-infiltrating lymphocytes, and clinical outcome in patients with surgically resected esophageal cancer. Ann Surg 269:471–478. https://doi.org/10.1097/SLA.0000000000002616CrossRefPubMed

Yamaki S, Yanagimoto H, Tsuta K, Ryota H, Kon M (2017) PD-L1 expression in pancreatic ductal adenocarcinoma is a poor prognostic factor in patients with high CD8(+) tumor-infiltrating lymphocytes: highly sensitive detection using phosphor-integrated dot staining. Int J Clin Oncol 22:726–733. https://doi.org/10.1007/s10147-017-1112-3CrossRefPubMedPubMedCentral

Zhai L, Ladomersky E, Lauing KL et al (2017) Infiltrating T cells increase IDO1 expression in glioblastoma and contribute to decreased patient survival. Clin Cancer Res 23:6650–6660. https://doi.org/10.1158/1078-0432.CCR-17-0120CrossRefPubMedPubMedCentral

Zhou Y, Shi D, Miao J et al (2017) PD-L1 predicts poor prognosis for nasopharyngeal carcinoma irrespective of PD-1 and EBV-DNA load. Sci Rep 7:43627. https://doi.org/10.1038/srep43627CrossRefPubMedPubMedCentral

Title: PD-L1 and IDO1 expression and tumor-infiltrating lymphocytes in osteosarcoma patients: comparative study of primary and metastatic lesions
Authors: Yu Toda
Kenichi Kohashi
Yuichi Yamada
Masato Yoshimoto
Shin Ishihara
Yoshihiro Ito
Takeshi Iwasaki
Hidetaka Yamamoto
Yoshihiro Matsumoto
Yasuharu Nakashima
Masaaki Mawatari
Yoshinao Oda
Publication date: 01-10-2020
Publisher: Springer Berlin Heidelberg
Keywords: osteosarcoma
Osteosarcoma
Cytostatic Therapy
Published in: Journal of Cancer Research and Clinical Oncology / Issue 10/2020
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-020-03242-6

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits

Illustration of figure on mountain summit/© Orapun / Stock.adobe.com, STEP AAG HeroTeaserCollection image/© Tarek / Generated with AI / Stock.adobe.com, ACC 2024 Pediatric and Congenital Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Pulmonary Vascular Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Valvular Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 HF and Cardiomyopathies: Year in Review/© 2024 American College of Cardiology, Woman out walking/© Seventyfour / stock.adobe.com (symbolic image with model), Woman checking smartwatch /© saltdium / stock.adobe.com (symbolic image with model), Cardiac catheterization/© Damian / stock.adobe.com

At a glance: The STEP trials

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 10/2020

Effects of alpha-fetoprotein on the occurrence and progression of hepatocellular carcinoma

Dynamics in treatment response and disease progression of metastatic colorectal cancer (mCRC) patients with focus on BRAF status and primary tumor location: analysis of untreated RAS-wild-type mCRC patients receiving FOLFOXIRI either with or without panitumumab in the VOLFI trial (AIO KRK0109)

Analyses of expressions and prognostic values of Polo-like kinases in non-small cell lung cancer

Aberrant DNA methylation results in altered gene expression in non-alcoholic steatohepatitis-related hepatocellular carcinomas

The effect of proton pump inhibitors on survival outcomes in advanced hepatocellular carcinoma treated with sorafenib

Systematic review and network meta-analyses of third-line treatments for metastatic colorectal cancer

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

Highlights from the ACC 2024 Congress

ACC 2024 Congress Coverage