Characterization of PD-1/PD-L1 immune checkpoint expression in soft tissue sarcomas
Inhibitors of the programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) immune checkpoint system are used for treating various malignancies. However, evidence on their use in soft tissue sarcomas (STS) is limited. This study aimed to retrospectively investigate the relationship between the expression of PD-1/PD-L1 and related antigens in STS, and their association with clinical characteristics. Immunostaining for CD4, CD8, PD-1, PD-L1, IL-2, and IFN-γ was performed using pathological specimens harvested at the time of biopsy from 10 patients with undifferentiated pleomorphic sarcoma (UPS), nine with myxofibrosarcoma (MFS), and three with malignant peripheral nerve sheath tumor (MPNST) who were treated at our hospital. Subsequently, the positive immunostaining cell rates were calculated. We also examined the correlation between each immune positive cell rate and age, tissue grade, size, and maximum standardized uptake (SUV-max) values. The 3-year event-free survival (EFS) and overall survival (OS) rates were compared between the positive and negative groups (positive rate >10%; negative <10%) for various immune stains. The positive rates were also compared between the presence and absence of events groups. There was positive staining for the immune checkpoint molecules in every STS type except for PD-1 in MPNST. CD4, CD8, and PD-1 stained lymphocytes in close proximity to the tumor in adjacent tissue sections. A positive correlation was observed between the positive cell rates of each immune component including inflammatory cytokines such as IL-2 and IFN-γ. Additionally, the clinical features positively correlated with the positive PD-1/PD-L1 expression rates. No significant differences in the 3-EFS and OS rates was observed between the PD-1/PD-L1 positive and negative groups. Our results suggest that an inducible immune checkpoint mechanism may be involved in UPS, MFS, and MPNST.
Fletcher CD, Lazar AJ, Baldini EH, Messiou C, Blay JY, Pollock RE, et al. WHO Classification of Tumors of Soft Tissue and Bone. Antonescu CR (eds). 5th ed. IARC Publications, Lyon: 2020. p. 6-12.
Penel N, Coindre JM, Giraud A, Terrier P, Ranchere-Vince D, Collin F, et al. Presentation and outcome of frequent and rare sarcoma histologic subtypes: A study of 10,262 patients with localized visceral/soft tissue sarcoma managed in reference centers. Cancer 2018;124:1179-87.
Clark MA, Fisher C, Judson I, Thomas JM. Soft-tissue sarcomas in adults. N Engl J Med 2005;353:701-11.
Tanaka K, Mizusawa J, Fukuda H, Araki N, Chuman H, Takahashi M, et al. Perioperative chemotherapy with ifosfamide and doxorubicin for high-grade soft tissue sarcomas in the extremities (JCOG0304). Jpn J Clin Oncol 2015;45:555-61.
Davis EJ, Chugh R, Zhao L, Lucas DR, Biermann JS, Zalupski MM, et al. A randomized open-label phase II study of neoadjuvant doxorubicin and ifosfamide versus gemcidabine and docetaxel in patients with localized, high risk, soft tissue sarcoma. Eur J Cancer 2015;51:1794-802.
van der Graaf WT, Blay JY, Chawla SP, Kim DW, Bui-Nguyen B, Casali PG, et al. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 2012;379:1879-86.
Kawai A, Araki N, Sugiura H, Ueda T, Yonemoto T, Takahashi M, et al. Trabectedin monotherapy after standard chemotherapy versus best supportive care in patients with advanced, translocation-related sarcoma: a randomised, open-label, phase 2 study. Lancet Oncol 2015;16:406-16.
Schöffski P, Chawla S, Maki RG, Italiano A, Gelderblom H, Choy E, et al. Eribulin versus dacarbazine in previously treated patients with advanced liposarcoma or leiomyosarcoma: a randomised, open-label, multicentre, phase 3 trial. Lancet 2016;387:1629-37.
Stefanovski PD, Bidoli E, De Paoli A, Buonadonna A, Boz G, Libra M, et al. Prognostic factors in soft tissue sarcomas: a study of 395 patients. Eur J Surg Oncol 2002;28:153-64.
Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 2002;8:793-800.
Ghebeh H, Mohammed S, Al-Omair A, Qattan A, Lehe C, Al-Qudaihi G, et al. The B7-H1 (PD-L1) T lymphocyte-inhibitory molecule is expressed in breast cancer patients with infiltrating ductal carcinoma: correlation with important high-risk prognostic factors. Neoplasia 2006;8:190-98.
Ohigashi Y, Sho M, Yamada Y, Tsurui Y, Hamada K, Ikeda N, et al. Clinical significance of programmed death-1 ligand-1 and programmed death-1 ligand-2 expression in human esophageal cancer. Clin Cancer Res 2005;11:2947-53.
Gong J, Chehrazi-Raffle A, Reddi S, Salgia R. Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: a comprehensive review of registration trials and future considerations. J Immunother Cancer 2018;6:8.
Mahoney KM, Freeman GJ, McDermott DF. The Next Immune-Checkpoint Inhibitors: PD-1/PD-L1 Blockade in Melanoma. Clin Ther 2015;37:764-82.
Oike N, Kawashima H, Ogose A, Hotta T, Hatano H, Ariizumi T, et al. Prognostic impact of the tumor immune microenvironment in synovial sarcoma. Cancer Sci 2018;109:3043-54.
Boxberg M, Steiger K, Lenze U, Rechl H, von Eisenhart-Rothe R, Wörtler K, et al. 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 2017;7:e1389366.
D'Angelo SP, Mahoney MR, Van Tine BA, Atkins J, Milhem MM, Jahagirdar BN, et al. Nivolumab with or without ipilimumab treatment for metastatic sarcoma (Alliance A091401): two open-label, non-comparative, randomised, phase 2 trials. Lancet Oncol 2018;19:416-26.
Burgess MA, Bolejack V, Van Tine BA, Schuetze S, Hu J, D'Angelo SP, et al. Multicenter phase II study of pembrolizumab (P) in advanced soft tissue (STS) and bone sarcomas (BS): Final results of SARC028 and biomarker analyses. J Clin Oncol 2017;35:suppl-11008.
D'Angelo SP, Shoushtari AN, Keohan ML, Dickson MA, Gounder MM, Chi P, et al. Combined KIT and CTLA-4 Blockade in Patients with Refractory GIST and Other Advanced Sarcomas: A Phase Ib Study of Dasatinib plus Ipilimumab. Clin Cancer Res 2017;23:2972-80.
Ogura K, Hosoda F, Arai Y, Nakamura H, Hama N, Totoki Y, et al. Integrated genetic and epigenetic analysis of myxofibrosarcoma. Nat Commun 2018;9:2765.
Widemann BC, Italiano A. Biology and management of undifferentiated pleomorphic sarcoma, myxofibrosarcoma, and malignant peripheral nerve sheath tumors: State of the art and perspectives. J Clin Oncol 2018;36:160-7.
Kakavand H, Wilmott JS, Long GV, Scolyer RA. Targeted therapies and immune checkpoint inhibitors in the treatment of metastatic melanoma patients: a guide and update for pathologists. Pathology 2016;48:194-202.
Gundle KR, Kafchinski L, Gupta S, Griffin AM, Dickson BC, Chung PW, et al. Analysis of margin classification systems for assessing the risk of local recurrence after soft tissue sarcoma resection. J Clin Oncol 2018;36:704-9.
Orth MF, Buecklein VL, Kampmann E, Subklewe M, Noessner E, Cidre-Aranaz F, et al. A comparative view on the expression patterns of PD-L1 and PD-1 in soft tissue sarcomas Cancer Immunol Immunother 2020;69:1353-62.
Kim C, Kim EK, Jung H, Chon HJ, Han JW, Shin KH, et al. Prognostic implications of PD-L1 expression in patients with soft tissue sarcoma. BMC Cancer 2016;16:434.
Paydas S, Bagir EK, Deveci MA, Gonlusen G. Clinical and prognostic significance of PD-1 and PD-L1 expression in sarcomas. Med Oncol 2016;33:93.
van Erp AEM, Versleijen-Jonkers YMH, Hillebrandt-Roeffen MHS, van Houdt L, Gorris MAJ, van Dam LS, et al. Expression and clinical association of programmed cell death-1, programmed death-ligand-1 and CD8+ lymphocytes in primary sarcomas is subtype dependent. Oncotarget 2017;8:71371-84.
Boxberg M, Steiger K, Lenze U, Rechl H, von Eisenhart-Rothe R, Wörtler K, et al. 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 2017;7:e1389366.
Pollack SM, He Q, Yearley JH, Emerson R, Vignali M, Zhang Y, et al. T-cell infiltration and clonality correlate with programmed cell death protein 1 and programmed death-ligand 1 expression in patients with soft tissue sarcomas. Cancer 2017;123:3291-304.
Budczies J, Mechtersheimer G, Denkert C, Klauschen F, Mughal SS, Chudasama P, et al. PD-L1 (CD274) copy number gain, expression, and immune cell infiltration as candidate predictors for response to immune checkpoint inhibitors in soft-tissue sarcoma. Oncoimmunology 2017;6:e1279777.
D'Angelo SP, Shoushtari AN, Agaram NP, Kuk D, Qin LX, Carvajal RD, et al. Prevalence of tumor-infiltrating lymphocytes and PD-L1 expression in the soft tissue sarcoma microenvironment. Hum Pathol 2015;46:357-65.
Davis LE, Nicholls LA, Babiker HM, Liau J, Mahadevan D. PD-1 Inhibition achieves a complete metabolic response in a patient with malignant peripheral nerve sheath tumor. Cancer Immunol Res 2019;7:1396-400.
Shurell E, Singh AS, Crompton JG, Jensen S, Li Y, Dry S, et al. Characterizing the immune microenvironment of malignant peripheral nerve sheath tumor by PD-L1 expression and presence of CD8+ tumor infiltrating lymphocytes. Oncotarget 2016;7:64300-8.
Gambichler T, Koim S, Wrobel M, Käfferlein HU, Brüning T, Stockfleth E, et al. Expression of Programmed Cell Death Proteins in Kaposi Sarcoma and Cutaneous Angiosarcoma. J Immunother 2020;43:169-74.
Miyake M, Oda Y, Nishimura N, Morizawa Y, Ohnishi S, Hatakeyama K, et al. Integrative assessment of clinicopathological parameters and the expression of PD-L1, PD-L2 and PD-1 in tumor cells of retroperitoneal sarcoma. Oncol Lett 2020;20:190.
Wunder JS, Lee MJ, Nam J, Lau BY, Dickson BC, Pinnaduwage D, et al. Osteosarcoma and soft-tissue sarcomas with an immune infiltrate express PD-L1: relation to clinical outcome and Th1 pathway activation. Oncoimmunology 2020;9:1737385.
Ishihara S, Iwasaki T, Kohashi K, Yamada Y, Toda Y, Ito Y, et al. The association between the expression of PD-L1 and CMTM6 in undifferentiated pleomorphic sarcoma. J Cancer Res Clin Oncol 2021;147:2003-11.
Ribas A, Hu-Lieskovan S. What does PD-L1 positive or negative mean? J Exp Med 2016;213:2835-40.
Liang SC, Latchman YE, Buhlmann JE, Tomczak MF, Horwitz BH, Freeman GJ, et al. Regulation of PD-1, PD-L1, and PD-L2 expression during normal and autoimmune responses. Eur J Immunol 2003;33:2706-16.
Shrikant P, Khoruts A, Mescher MF. CTLA-4 blockade reverses CD8+ T cell tolerance to tumor by a CD4+ T cell- and IL-2-dependent mechanism. Immunity 1999;11:483-93.
Tran DQ, Glass DD, Uzel G, Darnell DA, Spalding C, Holland SM, et al. Analysis of Adhesion Molecules, Target Cells, and Role of IL-2 in Human FOXP3+ Regulatory T Cell Suppressor Function. J Immunol 2009;1822929-38.
Schietinger A, Greenberg PD. Tolerance and exhaustion: defining mechanisms of T cell dysfunction. Trends Immunol 2014;35:51-60.
Iqbal N, Shukla NK, Deo SV, Agarwala S, Sharma DN, Sharma MC, et al. Prognostic factors affecting survival in metastatic soft tissue sarcoma: an analysis of 110 patients. Clin Transl Oncol 2016;18:310-6.
Coindre JM, Terrier P, Bui NB, Bonichon F, Collin F, Le Doussal V, et al. Prognostic factors in adult patients with locally controlled soft tissue sarcoma. A study of 546 patients from the French Federation of Cancer Centers Sarcoma Group. J Clin Oncol 1996;14:869-77.
Hong SP, Lee SE, Choi YL, Seo SW, Sung KS, Koo HH, et al. Prognostic value of 18F-FDG PET/CT in patients with soft tissue sarcoma: comparisons between metabolic parameters. Skeletal Radiol 2014;43:641-8.
Lahat G, Dhuka AR, Lahat S, Lazar AJ, Lewis VO, Lin PP, et al. Complete soft tissue sarcoma resection is a viable treatment option for select elderly patients. Ann Surg Oncol 2009;16:2579-86.
- Abstract views: 775
- PDF: 98
- HTML: 0
Copyright (c) 2021 The Author(s)
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.