PD‑L1 and IDO‑1 expression in undifferentiated pleomorphic sarcoma: The associations with tumor infiltrating lymphocytes, dMMR and HLA class I

Ishihara,Shin; Yamada,Yuichi; Iwasaki,Takeshi; Yoshimoto,Masato; Toda,Yu; Kohashi,Kenichi; Yamamoto,Hidetaka; Matsumoto,Yoshihiro; Nakashima,Yasuharu; Oda,Yoshinao

doi:10.3892/or.2020.7837

PD‑L1 and IDO‑1 expression in undifferentiated pleomorphic sarcoma: The associations with tumor infiltrating lymphocytes, dMMR and HLA class I

Authors:
- Shin Ishihara
- Yuichi Yamada
- Takeshi Iwasaki
- Masato Yoshimoto
- Yu Toda
- Kenichi Kohashi
- Hidetaka Yamamoto
- Yoshihiro Matsumoto
- Yasuharu Nakashima
- Yoshinao Oda
View Affiliations

Affiliations: Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812‑8582, Japan, Department of Orthopedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812‑8582, Japan
Published online on: November 5, 2020 https://doi.org/10.3892/or.2020.7837
Pages: 379-389

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The prognosis of undifferentiated pleomorphic sarcoma (UPS) is generally unfavorable. Recently, clinical trials such as SARC028 demonstrated the utility of cancer immunotherapy for soft tissue sarcomas. The aim of the present study was to assess the expression of PD‑L1 and IDO‑1 as prognostic factors and therapeutic targets. A total of 52 primary UPS cases were retrieved and two UPS cell lines were utilized for supplementary analysis. Immunohistochemical staining of anti‑PD‑L1 (28‑8), IDO‑1, CD8, CD4, CD3, HLA class I, MSH2, MSH6, MLH1 and PMS2 was carried out. Immunohistochemically, 19 of 52 (36.5%) cases showed PD‑L1 expression at least focally (≥1%) and 5 of 52 (9.62%) showed strong PD‑L1 expression (≥50%). Overall, 25 of 52 (48.1%) cases expressed IDO‑1 (≥1%). Two tumors were evaluated as having deficient mismatch repair and six tumors as having the loss of HLA class I. PD‑L1 expression (≥1%) was significantly related to the infiltration of CD8‑ and CD3‑positive lymphocytes, but strong PD‑L1 expression (≥50%) did not present a significant relationship with tumor‑infiltrating lymphocytes. IDO‑1 expression was also associated with CD8‑, CD4‑, and CD3‑positive lymphocytes. In vitro, both PD‑L1 and IDO‑1 were induced by IFN‑γ stimulation. In survival analysis, strong PD‑L1 expression (≥50%) was a significant poor prognostic factor, while IDO‑1 expression (≥1%) was a favorable one. In conclusion, UPS was shown to frequently express PD‑L1 and IDO‑1. It was suggested that PD‑L1 expression (≥50%) and IDO‑1 expression are poor and favorable prognostic factors of UPS patients, respectively.

View Figures

View References

1	The International Agency for Research on Cancer (IARC), ; Fletcher CDM, Chibon F and Mertens F: Pathology and genetics of tumours of soft tissue and bone (IARC WHO Classification of Tumours). IARC Press; Lyon: pp. 235–238. 2013
2	Gronchi A, Palmerini E, Quagliuolo V, Broto JM, Pousa AL, Grignani G, Brunello A, Blay JY, Tendero O, Beveridge RD, et al: Neoadjuvant chemotherapy in high-risk soft tissue sarcomas: Final results of a randomized trial from Italian (ISG), Spanish (GEIS), French (FSG), and Polish (PSG) sarcoma groups. J Clin Oncol. 1:2178–2186. 2020. View Article : Google Scholar
3	Kim JH, Park HS, Heo SJ, Kim SK, Han JW, Shin KH, Kim SH, Hur H, Kim KS, Choi YD, et al: Differences in the efficacies of pazopanib and gemcitabine/docetaxel as second-line treatments for metastatic soft tissue sarcoma. Oncology. 96:59–69. 2019. View Article : Google Scholar
4	Nakamura T, Tsukushi S, Asanuma K, Katagiri H, Ikuta K, Nagano A, Kozawa E, Yamada S, Shido Y, Yamada K, et al: The clinical outcome of eribulin treatment in Japanese patients with advanced soft tissue sarcoma: A tokai musculoskeletal oncology consortium study. Clin Exp Metastasis. 36:343–350. 2019. View Article : Google Scholar
5	Schalper KA, Carvajal-Hausdorf D, McLaughlin J, Altan M, Velcheti V, Gaule P, Sanmamed MF, Chen L, Herbst RS and Rimm DL: Differential expression and significance of PD-L1, IDO-1, and B7-H4 in human lung cancer. Clin Cancer Res. 15:370–378. 2017. View Article : Google Scholar
6	Pardoll DM: The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 22:252–264. 2012. View Article : Google Scholar
7	Syn NL, Teng MW, Mok TS and Soo RA: De-Novo and acquired resistance to immune checkpoint targeting. Lancet Oncol. 18:e731–e741. 2012. View Article : Google Scholar
8	Ready N, Hellmann MD, Awad MM, Otterson GA, Gutierrez M, Gainor JF, Borghaei H, Jolivet J, Horn L, Mates M, et al: First-Line nivolumab plus ipilimumab in advanced non-small-cell lung cancer (CheckMate 568): Outcomes by programmed death ligand 1 and tumor mutational burden as biomarkers. J Clin Oncol. 20:992–1000. 2019. View Article : Google Scholar
9	Tawbi HA, Burgess M, Bolejack V, Van Tine BA, Schuetze SM, Hu J, D'Angelo S, Attia S, Riedel RF, Priebat DA, et al: Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): A multicentre, two-cohort, single-arm, open-label, phase 2 trial. Lancet Oncol. 18:1493–1501. 2017. View Article : Google Scholar
10	Marabelle A, Le DT, Ascierto PA, Di Giacomo AM, De Jesus-Acosta A, Delord JP, Geva R, Gottfried M, Penel N, Hansen AR, et al: Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair-deficient cancer: Results from the phase II KEYNOTE-158 study. J Clin Oncol. 1:1–10. 2020. View Article : Google Scholar
11	Flores-Martin JF, Perea F, Exposito-Ruiz M, Carretero FJ, Rodriguez T, Villamediana M, Ruiz-Cabello F, Garrido F, Cózar-Olmo JM and Aptsiauri N: A combination of positive tumor HLA-I and negative PD-L1 expression provides an immune rejection mechanism in bladder cancer. Ann Surg Oncol. 26:2631–2639. 2019. View Article : Google Scholar
12	Johnson DB, Bordeaux J, Kim JY, Vaupel C, Rimm DL, Ho TH, Joseph RW, Daud AI, Conry RM, Gaughan EM, et al: Quantitative spatial profiling of PD-1/PD-L1 interaction and HLA-DR/IDO-1 predicts improved outcomes of anti-PD-1 therapies in metastatic melanoma. Clin Cancer Res. 1:5250–5260. 2018.
13	Munn DH and Mellor AL: Indoleamine 2,3 dioxygenase and metabolic control of immune responses. Trends Immunol. 34:137–143. 2013. View Article : Google Scholar
14	Prendergast GC, Smith C, Thomas S, Mandik-Nayak L, Laury- Kleintop L, Metz R and Muller AJ: Indoleamine 2,3-dioxygenase pathways of pathogenic inflammation and immune escape in cancer. Cancer Immunol Immunother. 63:721–735. 2014. View Article : Google Scholar
15	Long GV, Dummer R, Hamid O, Gajewski TF, Caglevic C, Dalle S, Arance A, Carlino MS, Grob JJ, Kim TM, et al: Epacadostat plus pembrolizumab versus placebo plus pembrolizumab in patients with unresectable or metastatic melanoma (ECHO-301/KEYNOTE-252): A phase 3, randomised, double-blind study. Lancet Oncol. 20:1083–1097. 2019. View Article : Google Scholar
16	Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, Chmielowski B, Spasic M, Henry G, Ciobanu V, et al: PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 27:568–571. 2014. View Article : Google Scholar
17	Sznol M and Chen L: Antagonist antibodies to PD-1 and B7-H1 (PD-L1) in the treatment of advanced human cancer. Clin Cancer Res. 19:1021–1034. 2013. View Article : Google Scholar
18	Yoshimoto M, Yamada Y, Ishihara S, Kohashi K, Toda Y, Ito Y, Yamamoto H, Furue M, Nakashima Y and Oda Y: Comparative study of myxofibrosarcoma with undifferentiated pleomorphic sarcoma: Histopathologic and clinicopathologic review. Am J Surg Pathol. 44:87–97. 2020. View Article : Google Scholar
19	Thway K, Flora R, Shah C, Olmos D and Fisher C: Diagnostic utility of p16, CDK4, and MDM2 as an immunohistochemical panel in distinguishing well-differentiated and dedifferentiated liposarcomas from other adipocytic tumors. Am J Surg Pathol. 36:462–469. 2012. View Article : Google Scholar
20	Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL and Trotti A: AJCC Cancer Staging Manual. 7th edition. Springer; St. Louis, MO: 2010
21	Volaric A, Gentzler R, Hall R, Mehaffey JH, Stelow EB, Bullock TN, Martin LW and Mills AM: Indoleamine-2,3-dioxygenase in non-small cell lung cancer: A targetable mechanism of immune resistance frequently coexpressed with PD-L1. Am J Surg Pathol. 42:1216–1223. 2018. View Article : Google Scholar
22	Herbst RS, Baas P, Kim DW, Felip E, Pérez-Gracia JL, Han JY, Molina J, Kim JH, Arvis CD, Ahn MJ, et al: Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): A randomised controlled trial. Lancet. 9:1540–1550. 2016. View Article : Google Scholar
23	Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, et al: Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 10:1823–1833. 2016. View Article : Google Scholar
24	Seeber A, Klinglmair G, Fritz J, Steinkohl F, Zimmer KC, Aigner F, Horninger W, Gastl G, Zelger B, Brunner A and Pichler R: High IDO-1 expression in tumor endothelial cells is associated with response to immunotherapy in metastatic renal cell carcinoma. Cancer Sci. 109:1583–1591. 2018. View Article : Google Scholar
25	Perea F, Bernal M, Sánchez-Palencia A, Carretero J, Torres C, Bayarri C, Gómez-Morales M, Garrido F and Ruiz-Cabello F: 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. 15:888–899. 2017. View Article : Google Scholar
26	Nakano K, Yamamoto H, Fujiwara M, Koga Y, Tsuruta S, Ihara E, Oki E, Nakamura M, Ogawa Y and Oda Y: Clinicopathologic and molecular characteristics of synchronous colorectal carcinoma with mismatch repair deficiency. Am J Surg Pathol. 42:172–182. 2018. View Article : Google Scholar
27	Yoo SH, Keam B, Ock CY, Kim S, Han B, Kim JW, Lee KW, Jeon YK, Jung KC, Chung EJ, et al: Prognostic value of the association between MHC class I downregulation and PD-L1 upregulation in head and neck squamous cell carcinoma patients. Sci Rep. 22:76802019. View Article : Google Scholar
28	Hakozaki M, Hojo H, Sato M, Tajino T, Yamada H, Kikuchi S and Abe M: Establishment and characterization of a new cell line, FPS-1, derived from human undifferentiated pleomorphic sarcoma, overexpressing epidermal growth factor receptor and cyclooxygenase-2. Anticancer Res. 26:3393–3401. 2006.
29	Nishio J, Iwasaki H, Nabeshima K, Ishiguro M, Isayama T and Naito M: Establishment of a new human pleomorphic malignant fibrous histiocytoma cell line, FU-MFH-2: Molecular cytogenetic characterization by multicolor fluorescence in situ hybridization and comparative genomic hybridization. J Exp Clin Cancer Res. 24:1532010. View Article : Google Scholar
30	Boxberg M, Steiger K, Lenze U, Rechl H, von Eisenhart-Rothe R, Wörtler K, Weichert W, Langer R and Specht K: PD-L1 and PD-1 and characterization of tumor-infiltrating lymphocytes in high grade sarcomas of soft tissue-prognostic implications and rationale for immunotherapy. Oncoimmunology. 20:e13893662017.
31	Burr ML, Sparbier CE, Chan YC, Williamson JC, Woods K, Beavis PA, Lam EY, Henderson MA, Bell CC, Stolzenburg S, et al: CMTM6 maintains the expression of PD-L1 and regulates anti-tumour immunity. Nature. 7:101–105. 2017. View Article : Google Scholar
32	Sun R, Limkin EJ, Vakalopoulou M, Dercle L, Champiat S, Han SR, Verlingue L, Brandao D, Lancia A, Ammari S, et al: A radiomics approach to assess tumour-infiltrating CD8 cells and response to anti-PD-1 or anti-PD-L1 immunotherapy: An imaging biomarker, retrospective multicohort study. Lancet Oncol. 19:1180–1191. 2018. View Article : Google Scholar
33	Patil PA, Blakely AM, Lombardo KA, Machan JT, Miner TJ, Wang LJ, Marwaha AS and Matoso A: Expression of PD-L1, indoleamine 2,3-dioxygenase and the immune microenvironment in gastric adenocarcinoma. Histopathology. 73:124–136. 2018. View Article : Google Scholar
34	Zheng C, You W, Wan P, Jiang X, Chen J, Zheng Y, Li W, Tan J and Zhang S: Clinicopathological and prognostic significance of PD-L1 expression in sarcoma: A systematic review and meta-analysis. Medicine (Baltimore). 97:e110042018. View Article : Google Scholar
35	Vasileios KA, Eward WC and Brigman BE: Surgical treatment and prognosis in patients with high-grade soft tissue malignant fibrous histiocytoma of the extremities. Arch Orthop Trauma Surg. 132:955–961. 2012. View Article : Google Scholar
36	Roland CL, May CD, Watson KL, Al Sannaa GA, Dineen SP, Feig R, Landers S, Ingram DR, Wang WL, Guadagnolo BA, et al: Analysis of clinical and molecular factors impacting oncologic outcomes in undifferentiated pleomorphic sarcoma. Ann Surg Oncol. 23:2220–2228. 2016. View Article : Google Scholar