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Journal of Cancer Research and Clinical Oncology

Erschienen in:

20.09.2020 | Original Article – Clinical Oncology

Association of PD-L1 and IDO1 expression with JAK–STAT pathway activation in soft-tissue leiomyosarcoma

verfasst von: Takeshi Iwasaki, Kenichi Kohashi, Yu Toda, Shin Ishihara, Yuichi Yamada, Yoshinao Oda

Erschienen in: Journal of Cancer Research and Clinical Oncology | Ausgabe 5/2021

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Abstract

Purpose

Therapies targeting the immune checkpoint molecules programmed death ligand 1 (PD-L1) and indoleamine 2,3-dioxygenase 1 (IDO1) have been explored in various malignant tumours. In this study, we examined the relationship between PDL-1, IDO1 and JAK2 expression and the roles of these signal pathways in soft tissue leiomyosarcoma (LMS).

Methods

The next-generation sequencing data of 53 patients with LMS were obtained from an online public database and were used to assess PD-L1, IDO1 and JAK2 gene amplification and mRNA expression. Then, we determined the relationship between JAK–STAT pathway activation and PD-L1 and IDO1 expression in a LMS cell line. In addition, immunohistochemical staining of 69 cases of LMS was performed for PD-L1, IDO1, TDO2 and phosphorylated JAK2 (pJAK2).

Results

Comprehensive gene expression analysis using microarray and RNA-Seq data revealed that PD-L1 and IDO1 mRNA expression positively correlated with JAK2 and STAT1 mRNA expression. Two of the 53 cases exhibited PD-L1 and JAK2 gene amplification; however, they were not related to their gene expression. LMS cell line analysis revealed that IFN-γ supplementation induced IDO1 and PD-L1 expression; these effects were suppressed by JAK inhibition. Immunohistochemical analysis of the resected specimens revealed that TDO2 expression positively correlated with pJAK2 (P = 0.0490) and IDO1 expression (P < 0.0001). PD-L1-positive specimens tended to express pJAK2; however, the relationship did not reach statistical significance (P = 0.1477).

Conclusion

The results suggest the possible feasibility of the combined inhibition of PD-1/PD-L1 or IDO1 with IFN-γ–JAK–STAT pathway inhibition to treat soft tissue LMS.

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Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, Schuster SJ, Millenson MM, Cattry D, Freeman GJ, Rodig SJ, Chapuy B, Ligon AH, Zhu L, Grosso JF, Kim SY, Timmerman JM, Shipp MA, Armand P (2015) PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med 372(4):311–319. https://doi.org/10.1056/NEJMoa1411087CrossRefPubMed

Atefi M, Avramis E, Lassen A, Wong DJ, Robert L, Foulad D, Cerniglia M, Titz B, Chodon T, Graeber TG, Comin-Anduix B, Ribas A (2014) Effects of MAPK and PI3K pathways on PD-L1 expression in melanoma. Clin Cancer Res 20(13):3446–3457. https://doi.org/10.1158/1078-0432.CCR-13-2797CrossRefPubMedCentralPubMed

Banzola I, Mengus C, Wyler S, Hudolin T, Manzella G, Chiarugi A, Boldorini R, Sais G, Schmidli TS, Chiffi G, Bachmann A, Sulser T, Spagnoli GC, Provenzano M (2018) Expression of indoleamine 2,3-dioxygenase induced by IFN-gamma and TNF-alpha as potential biomarker of prostate cancer progression. Front Immunol 9:1051. https://doi.org/10.3389/fimmu.2018.01051CrossRefPubMedCentralPubMed

Bellucci R, Martin A, Bommarito D, Wang K, Hansen SH, Freeman GJ, Ritz J (2015) Interferon-gamma-induced activation of JAK1 and JAK2 suppresses tumor cell susceptibility to NK cells through upregulation of PD-L1 expression. Oncoimmunology 4(6):e1008824. https://doi.org/10.1080/2162402X.2015.1008824CrossRefPubMedCentralPubMed

Brochez L, Chevolet I, Kruse V (2017) The rationale of indoleamine 2,3-dioxygenase inhibition for cancer therapy. Eur J Cancer 76:167–182. https://doi.org/10.1016/j.ejca.2017.01.011CrossRefPubMed

Budczies J, Denkert C, Gyorffy B, Schirmacher P, Stenzinger A (2017) Chromosome 9p copy number gains involving PD-L1 are associated with a specific proliferation and immune-modulating gene expression program active across major cancer types. BMC Med Genomics 10(1):74. https://doi.org/10.1186/s12920-017-0308-8CrossRefPubMedCentralPubMed

Cancer Genome Atlas Research Network (2017) Comprehensive and integrated genomic characterization of adult soft tissue sarcomas. Cell 171(4):950–965. https://doi.org/10.1016/j.cell.2017.10.014

Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, Jacobsen A, Byrne CJ, Heuer ML, Larsson E, Antipin Y, Reva B, Goldberg AP, Sander C, Schultz N (2012) The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov 2(5):401–404. https://doi.org/10.1158/2159-8290.CD-12-0095CrossRefPubMed

Chen IC, Lee KH, Hsu YH, Wang WR, Chen CM, Cheng YW (2016) Expression pattern and clinicopathological relevance of the indoleamine 2,3-Dioxygenase 1/Tryptophan 2,3-Dioxygenase protein in colorectal cancer. Dis Markers 2016:8169724. https://doi.org/10.1155/2016/8169724CrossRefPubMedCentralPubMed

Cheong JE, Sun L (2018) Targeting the IDO1/TDO2-KYN-AhR pathway for cancer immunotherapy–challenges and opportunities. Trends Pharmacol Sci 39(3):307–325. https://doi.org/10.1016/j.tips.2017.11.007CrossRefPubMed

D’Amato NC, Rogers TJ, Gordon MA, Greene LI, Cochrane DR, Spoelstra NS, Nemkov TG, D’Alessandro A, Hansen KC, Richer JK (2015) A TDO2-AhR signaling axis facilitates anoikis resistance and metastasis in triple-negative breast cancer. Cancer Res 75(21):4651–4664. https://doi.org/10.1158/0008-5472.CAN-15-2011CrossRefPubMedCentralPubMed

D’Angelo SP, Mahoney MR, Van Tine BA, Atkins J, Milhem MM, Jahagirdar BN, Antonescu CR, Horvath E, Tap WD, Schwartz GK, Streicher H (2018) Nivolumab with or without ipilimumab treatment for metastatic sarcoma (Alliance A091401): two open-label, non-comparative, randomised, phase 2 trials. Lancet Oncol 19(3):416–426. https://doi.org/10.1016/S1470-2045(18)30006-8CrossRefPubMedCentralPubMed

Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, Sun Y, Jacobsen A, Sinha R, Larsson E, Cerami E, Sander C, Schultz N (2013) Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal 6(269):pl1. https://doi.org/10.1126/scisignal.2004088CrossRefPubMedCentralPubMed

Garcia-Diaz A, Shin DS, Moreno BH, Saco J, Escuin-Ordinas H, Rodriguez GA, Zaretsky JM, Sun L, Hugo W, Wang X, Parisi G, Saus CP, Torrejon DY, Graeber TG, Comin-Anduix B, Hu-Lieskovan S, Damoiseaux R, Lo RS, Ribas A (2017) Interferon receptor signaling pathways regulating PD-L1 and PD-L2 expression. Cell Rep 19(6):1189–1201. https://doi.org/10.1016/j.celrep.2017.04.031CrossRefPubMedCentralPubMed

Grimer R, Judson I, Peake D, Seddon B (2010) Guidelines for the management of soft tissue sarcomas. Sarcoma 2010:506182. https://doi.org/10.1155/2010/506182CrossRefPubMedCentralPubMed

Heine A, Kristiansen G, Schild HH, Brossart P (2016) Successful treatment of refractory leiomyosarcoma with the PD-1 inhibitor nivolumab. Ann Oncol 27(9):1813–1814. https://doi.org/10.1093/annonc/mdw243CrossRefPubMed

Hellmann MD, Gettinger S, Chow LQM, Gordon M, Awad MM, Cha E, Gong X, Zhou G, Walker C, Leopold L, Heist RS (2020) Phase 1 study of epacadostat in combination with atezolizumab for patients with previously treated advanced nonsmall cell lung cancer. Int J Cancer 147(7):1963–1969. https://doi.org/10.1002/ijc.32951CrossRefPubMedCentralPubMed

Ishii T, Kohashi K, Ootsuka H, Iura K, Maekawa A, Yamada Y, Bekki H, Yoshimoto M, Yamamoto H, Iwamoto Y, Oda Y (2017) Comparison between retroperitoneal leiomyosarcoma and dedifferentiated liposarcoma. Pathol Res Pract 213(6):634–638CrossRefPubMed

Iwasaki T, Matsushita M, Nonaka D, Nagata K, Kato M, Kuwamoto S, Murakami I, Hayashi K (2016) Lower expression of CADM1 and higher expression of MAL in Merkel cell carcinomas are associated with Merkel cell polyomavirus infection and better prognosis. Hum Pathol 48:1–8. https://doi.org/10.1016/j.humpath.2015.09.030CrossRefPubMed

Iwasaki, T, Kohashi, K, Ohno, M, Taguchi, T, Oda, Y (2020) Establishment and characterization of a novel primitive yolk sac tumour cell line, TC587. Anticancer Res 40(2):759–766. https://doi.org/10.21873/anticanres.14007CrossRef

Kiyozumi Y, Baba Y, Okadome K, Yagi T, Ishimoto T, Iwatsuki M, Miyamoto Y, Yoshida N, Watanabe M, Komohara Y, Baba H (2019) IDO1 expression is associated with immune tolerance and poor prognosis in patients with surgically resected esophageal cancer. Ann Surg 269(6):1101–1108. https://doi.org/10.1097/SLA.0000000000002754CrossRefPubMed

Kozuma Y, Takada K, Toyokawa G, Kohashi K, Shimokawa M, Hirai F, Tagawa T, Okamoto T, Oda Y, Maehara Y (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

Lu X, He SY, Li Q, Yang H, Jiang X, Lin H, Chen Y, Qu W, Feng F, Bian Y, Zhou Y, Sun H (2018) Investigation of multi-target-directed ligands (MTDLs) with butyrylcholinesterase (BuChE) and indoleamine 2,3-dioxygenase 1 (IDO1) inhibition: the design, synthesis of miconazole analogues targeting Alzheimer’s disease. Bioorg Med Chem 26(8):1665–1674. https://doi.org/10.1016/j.bmc.2018.02.014CrossRefPubMed

Maekawa A, Kohashi K, Setsu N, Kuda M, Iura K, Ishii T, Matsunobu T, Nakatsura T, Iwamoto Y, Oda Y (2016) Expression of Forkhead box M1 in soft tissue leiomyosarcoma: clinicopathologic and in vitro study using a newly established cell line. Cancer Sci 107(1):95–102. https://doi.org/10.1111/cas.12846CrossRefPubMedCentralPubMed

Ninomiya S, Hara T, Tsurumi H, Hoshi M, Kanemura N, Goto N, Kasahara S, Shimizu M, Ito H, Saito K, Hirose Y, Yamada T, Takahashi T, Seishima M, Takami T, Moriwaki H (2011) Indoleamine 2,3-dioxygenase in tumor tissue indicates prognosis in patients with diffuse large B-cell lymphoma treated with R-CHOP. Ann Hematol 90(4):409–416. https://doi.org/10.1007/s00277-010-1093-zCrossRefPubMed

Opitz CA, Somarribas Patterson LF, Mohapatra SR, Dewi DL, Sadik A, Platten M, Trump S (2020) The therapeutic potential of targeting tryptophan catabolism in cancer. Br J Cancer 122(1):30–44. https://doi.org/10.1038/s41416-019-0664-6CrossRefPubMed

Ott PA, Hodi FS, Kaufman HL, Wigginton JM, Wolchok JD (2017) Combination immunotherapy: a road map. J Immunother Cancer 5:16. https://doi.org/10.1186/s40425-017-0218-5CrossRefPubMedCentralPubMed

Riesenberg R, Weiler C, Spring O, Eder M, Buchner A, Popp T, Castro M, Kammerer R, Takikawa O, Hatz RA, Stief CG, Hofstetter A, Zimmermann W (2007) Expression of indoleamine 2,3-dioxygenase in tumor endothelial cells correlates with long-term survival of patients with renal cell carcinoma. Clin Cancer Res 13(23):6993–7002. https://doi.org/10.1158/1078-0432.CCR-07-0942CrossRefPubMed

Riess C, Schneider B, Kehnscherper H, Gesche J, Irmscher N, Shokraie F, Classen CF, Wirthgen E, Domanska G, Zimpfer A, Struder D, Junghanss C, Maletzki C (2020) Activation of the Kynurenine pathway in human malignancies can be suppressed by the cyclin-dependent kinase inhibitor dinaciclib. Front Immunol 11:55. https://doi.org/10.3389/fimmu.2020.00055CrossRefPubMedCentralPubMed

Roemer MG, Advani RH, Ligon AH, Natkunam Y, Redd RA, Homer H, Connelly CF, Sun HH, Daadi SE, Freeman GJ, Armand P, Chapuy B, de Jong D, Hoppe RT, Neuberg DS, Rodig SJ, Shipp MA (2016) PD-L1 and PD-L2 genetic alterations define classical hodgkin lymphoma and predict outcome. J Clin Oncol 34(23):2690–2697. https://doi.org/10.1200/JCO.2016.66.4482CrossRefPubMedCentralPubMed

Rosenbaum MW, Gigliotti BJ, Pai SI, Parangi S, Wachtel H, Mino-Kenudson M, Gunda V, Faquin WC (2018) PD-L1 and IDO1 are expressed in poorly differentiated thyroid carcinoma. Endocr Pathol 29(1):59–67. https://doi.org/10.1007/s12022-018-9514-yCrossRefPubMedCentralPubMed

Setsu N, Kohashi K, Endo M, Yamamoto H, Tamiya S, Takahashi Y, Yamada Y, Ishii T, Matsuda S, Yokoyama R, Iwamoto Y, Oda Y (2013) Phosphorylation of signal transducer and activator of transcription 3 in soft tissue leiomyosarcoma is associated with a better prognosis. Int J Cancer 132(1):109–115. https://doi.org/10.1002/ijc.27655CrossRefPubMed

Smith LP, Bitler BG, Richer JK, Christenson JL (2019) Tryptophan catabolism in epithelial ovarian carcinoma. Trends Cancer Res 14:1–9PubMedCentralPubMed

Takada K, Shimokawa M, Tanaka K, Kohashi K, Haro A, Osoegawa A, Tagawa T, Azuma K, Okamoto I, Oda Y, Mori M (2019) Association between peripheral blood markers and immune-related factors on tumor cells in patients with resected primary lung adenocarcinoma. PLoS ONE 14(6):e0217991. https://doi.org/10.1371/journal.pone.0217991CrossRefPubMedCentralPubMed

Thiem A, Hesbacher S, Kneitz H, di Primio T, Heppt MV, Hermanns HM, Goebeler M, Meierjohann S, Houben R, Schrama D (2019) IFN-gamma-induced PD-L1 expression in melanoma depends on p53 expression. J Exp Clin Cancer Res 38(1):397. https://doi.org/10.1186/s13046-019-1403-9CrossRefPubMedCentralPubMed

Toro JR, Travis LB, Wu HJ, Zhu K, Fletcher CD, Devesa SS (2006) Incidence patterns of soft tissue sarcomas, regardless of primary site, in the surveillance, epidemiology and end results program, 1978-2001: an analysis of 26,758 cases. Int J Cancer 119(12):2922–2930. https://doi.org/10.1002/ijc.22239CrossRefPubMed

Van Glabbeke M, van Oosterom AT, Oosterhuis JW, Mouridsen H, Crowther D, Somers R, Verweij J, Santoro A, Buesa J, Tursz T (1999) Prognostic factors for the outcome of chemotherapy in advanced soft tissue sarcoma: an analysis of 2,185 patients treated with anthracycline-containing first-line regimens–a European organization for research and treatment of cancer soft tissue and bone sarcoma group study. J Clin Oncol 17(1):150–157. https://doi.org/10.1200/JCO.1999.17.1.150CrossRefPubMed

Wardhani LO, Matsushita M, Iwasaki T, Kuwamoto S, Nonaka D, Nagata K, Kato M, Kitamura Y, Hayashi K (2019) Expression of the IDO1/TDO2-AhR pathway in tumor cells or the tumor microenvironment is associated with Merkel cell polyomavirus status and prognosis in Merkel cell carcinoma. Hum Pathol 84:52–61. https://doi.org/10.1016/j.humpath.2018.09.003CrossRefPubMed

Xi C, Wencheng Z, Dong Q, Yong G, Cihui Y, Yuwen W, Hualei Z, Puchun E, Qingsong P, Ping W (2019) Tumor regression after combination of radiation and PD-1 antibody nivolumab treatment in a patient with metastatic mediastinal leiomyosarcoma: a case report. Cancer Biol Ther 20(4):408–412. https://doi.org/10.1080/15384047.2018.1537577CrossRefPubMed

Titel: Association of PD-L1 and IDO1 expression with JAK–STAT pathway activation in soft-tissue leiomyosarcoma
verfasst von: Takeshi Iwasaki
Kenichi Kohashi
Yu Toda
Shin Ishihara
Yuichi Yamada
Yoshinao Oda
Publikationsdatum: 20.09.2020
Verlag: Springer Berlin Heidelberg
Erschienen in: Journal of Cancer Research and Clinical Oncology / Ausgabe 5/2021
Print ISSN: 0171-5216
Elektronische ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-020-03390-9

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Association of PD-L1 and IDO1 expression with JAK–STAT pathway activation in soft-tissue leiomyosarcoma