PROGNOSTIC IMPLICATIONS OF PD-L1 EXPRESSION AND LOSS OF PTEN IN PATIENTS WITH RHABDOMYOSARCOMA, EWING’S SARCOMA AND OSTEOSARCOMA
DOI:
https://doi.org/10.15407/exp-oncology.2023.03.337Keywords:
PD-L1, PTEN, Ewing’s sarcoma, osteosarcoma, rhabdomyosarcomaAbstract
Background. In children, osteosarcoma (OS), Ewing’s sarcoma (ES), and rhabdomyosarcoma (RMS) are the most common sarcomas. A link between the anti-programmed death ligand-1 PD-L1 and the tumor suppressor phosphatase and tensin homologue (PTEN) expression has been described in many tumors. The aim of this work is to determine clinicopathological relationships and the possible prognostic significance of PD-L1 and PTEN expression in rhabdomyosarcoma (RMS), Ewing's sarcoma (ES), and osteosarcoma (OS). Materials and Methods. Expression of PD-L1 and PTEN were examined by immunohistochemistry in 45 archival RMS, ES, and OS cases. Results. The positive expression of PD-L1 was found in 16.7% and 31.6% of ES and OS, respectively. The negative PD-L1 was related to a substantially longer survival in ES cases (p = 0.045), but positive PD-L1 expression was significantly associated with the increased tumor stage and vascular invasion in the OS cases (p = 0.005 and p = 0.002), respectively. On the other hand, PTEN loss was strongly associated with deep tumor, high tumor grade, and recurrence in RMS (p = 0.002, p = 0.045, and p = 0.026, respectively). However, PTEN loss was significantly absent in ES as tumor grade increased (p = 0.031). It is noteworthy that tumor recurrence, the loss of PTEN, and positive PD-L1 were all considered predictive factors in OS patients (p = 0.045, p = 0.032, and p = 0.02, respectively). Conclusions. In children, OS and ES have positive PD-L1 expression, which has an independent unfavorable prognostic effect and raises the possibility of using PD-L1 as a therapeutic target. OS, ES, and RMS prognosis are all predicted by PTEN loss.
References
Keegan TH, Ries LA, Barr RD, et al. Comparison of cancer survival trends in the United States of adolescents and young adults with those in children and older adults. Cancer. 2016;122(7):1009-1016. https://doi.org/10.1002/ Cncr.29869
Huwait H, Almaghrabi H, Gayyed M, et al. Potential for using EGFR expression in rhabdomyosarcoma, osteosarcoma and ewing’s sarcoma: clinicopathological and prognostic significance. Sci J King Faisal Univ. 2022:1-5. https://doi.org/10.37575/B/Med/220003.
Chen S, Huang H, He S, et al. Spindle cell lipoma: clinicopathologic characterization of 40 cases. Int J Clin Exp Pathol. 2019;12(7):2613-2621. Pubmed PMID: 31934089; Pubmed Central PMCID: PMC6949558.
Wunder JS, Lee MJ, Nam J, et al. Osteosarcoma and soft-tissue sarcomas with an immune infiltrate express PD- L1: relation to clinical outcome and Th1 pathway activation. Oncoimmunol. 2020;9(1):1737385. https://doi.org/1 0.1080/2162402X.2020.1737385
Choi JH, Ro JY. The 2020 WHO classification of tumors of soft tissue: selected changes and new entities. Adv Anatom Pathol. 2021;28(1):44-58. https://doi.org/10.1097/PAP.0000000000000284
Patel SP, Kurzrock R. PD-L1 expression as a predictive biomarker in cancer immunotherapy. Mol Cancer Ther. 2015;14(4):847-856. https://doi.org/10.1158/1535-7163.Mct-14-0983
Kerr KM, Hirsch FR. Programmed death ligand-1 immunohistochemistry: friend or foe? Arch Pathol Lab Med. 2016;140(4):326-331. https://doi.org/10.5858/Arpa.2015-0522-SA
Gabrych A, Peksa R, Kunc M, et al. The PD-L1/PD-1 axis expression on tumor-infiltrating immune cells and tumor cells in pediatric rhabdomyosarcoma. Pathol Res Pract. 2019;215(12):152700. https://doi.org/10.1016/J. Prp.2019.152700
Cunningham CR, Dodd L, Esebua M, et al. PD-L1 expression in sarcomas: an immunohistochemical study and review of the literature. Ann Diagn Pathol. 2021;55:151823. https://doi.org/10.1016/J.Anndiagpath.2021.151823
Kim C, Kim EK, Jung H, et al. Prognostic implications Of PD-L1 expression in patients with soft tissue sarcoma.
BMC Cancer. 2016;16:434. https://doi.org/10.1186/S12885-016-2451-6.
Rennier K, Shin WJ, Krug E, et al. Chemerin reactivates PTEN and suppresses PD-L1 in tumor cells via modulation of a novel CMKLR1-mediated signaling cascade. Clin Cancer Res. 2020;26(18):5019-5035. https://doi. org/10.1158/1078-0432.CCR-19-4245
Xia W, Zhu J, Tang Y, et al. PD-L1 inhibitor regulates the Mir-33a-5p/PTEN signaling pathway and can be targeted to sensitize glioblastomas to radiation. Front Oncol. 2020;10:821. https://doi.org/10.3389/Fonc.2020.00821
Liu Z, Wen J, Wu C, et al. Microrna-200a induces immunosuppression by promoting PTEN-mediated PD-L1 up- regulation in osteosarcoma. Aging _(Albany NY). 2020;12(2):1213-1236. https://doi.org/10.18632/Aging.102679
Papa A, Pandolfi PP. The PTEN-PI3K axis in cancer. Biomolecules. 2019;9(4):153. https://doi.org/10.3390/Biom9040153
Cretella D, Digiacomo G, Giovannetti E, et al. PTEN alterations as a potential mechanism for tumor cell escape from PD-1/PD-L1 inhibition. Cancers (Basel). 2019;11(9):1318. https://doi.org/10.3390/Cancers11091318
George S, Miao D, Demetri GD, et al. Loss of PTEN is associated with resistance to anti-PD-1 checkpoint block- ade therapy in metastatic uterine leiomyosarcoma. Immunity. 2017;46(2):197-204. https://doi.org/10.1016/J.Immuni.2017.02.001
Vargas AC, Maclean FM, Sioson L, et al. Prevalence of PD-L1 expression in matched recurrent and/or metastatic sarcoma samples and in a range of selected sarcomas subtypes. Plos One. 2020;15(4):E0222551. https://doi.org/10.1371/Journal.Pone.0222551
Quattrone A, Wozniak A, Dewaele B, et al. Frequent mono-allelic loss associated with deficient PTEN expression in imatinib-resistant gastrointestinal stromal tumors. Mod Pathol. 2014;27(11):1510-1520. https://doi.org/10.1038/Modpathol.2014.53
Linch M, Miah AB, Thway K, et al. Systemic treatment of soft-tissue sarcoma-gold standard and novel therapies. Nat Rev Clin Oncol. 2014;11(4):187-202. https://doi.org/10.1038/Nrclinonc.2014.26
Frezza AM, Stacchiotti S, Gronchi A. Systemic treatment in advanced soft tissue sarcoma: what is standard, what is new. BMC Med. 2017;15(1):109. https://doi.org/10.1186/S12916-017-0872-Y
Boxberg M, Steiger K, Lenze U, 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. Oncoimmunol. 2018;7(3):E1389366. https://doi.org/10.1080/2162402X.2017.1389366
Zheng C, Tang F, Min L, et al. PTEN In osteosarcoma: recent advances and the therapeutic potential. Biochim Biophys Acta Rev Cancer. 2020;1874(2):188405. https://doi.org/10.1016/J.Bbcan.2020.188405
Bertolini G, Bergamaschi L, Ferrari A, et al. PD-L1 assessment in pediatric rhabdomyosarcoma: a pilot study. BMC Cancer. 2018;18(1):652. https://doi.org/10.1186/S12885-018-4554-8
Machado I, Lopez-Guerrero JA, Scotlandi K, et al. Immunohistochemical analysis and prognostic significance of PD-L1, PD-1, and CD8+ tumor-infiltrating lymphocytes in Ewing's sarcoma family of tumors (ESFT). Virchows Arch. 2018;472(5):815-824. https://doi.org/10.1007/S00428-018-2316-2
Shen JK, Cote GM, Choy E, et al. Programmed cell death ligand 1 expression in osteosarcoma. Cancer Immunol Res. 2014;2(7):690-698. https://doi.org/10.1158/2326-6066.CIR-13-0224
Paydas S, Bagir EK, Deveci MA, et al. Clinical and prognostic significance of PD-1 and PD-L1 expression in sarcomas. Med Oncol. 2016;33(8):93. https://doi.org/10.1007/S12032-016-0807-Z
Liu P, Xiao Q, Zhou B, et al. Prognostic significance of programmed death ligand 1 expression and tumor-in- filtrating lymphocytes in axial osteosarcoma. World Neurosurg. 2019;129:E240-E254. https://doi.org/10.1016/J.Wneu.2019.05.121
Torabi A, Amaya CN, Wians FH, et al. PD-1 and PD-L1 expression in bone and soft tissue sarcomas. Pathology. 2017;49(5):506-513. https://doi.org/10.1016/J.Pathol.2017.05.003
Park BV, Freeman ZT, Ghasemzadeh A, et al. Tgfbeta1-mediated SMAD3 enhances PD-1 expression on antigen-specific T cells in cancer. Cancer Discov. 2016;6(12):1366-1381. https://doi.org/10.1158/2159-8290.CD-15-1347
Song M, Chen D, Lu B, et al. PTEN loss increases PD-L1 protein expression and affects the correlation between PD-L1 expression and clinical parameters in colorectal cancer. Plos One. 2013;8(6):E65821. https://doi.org/10.1371/Journal.Pone.0065821
Schaefer IM, Lundberg MZ, Demicco EG, et al. Relationships between highly recurrent tumor suppressor alterations in 489 leiomyosarcomas. Cancer. 2021;127(15):2666-2673. https://doi.org/10.1002/Cncr.33542.
Lee ATJ, Thway K, Huang PH, et al. Clinical and molecular spectrum of liposarcoma. J Clin Oncol. 2018;36(2):151-159. https://doi.org/10.1200/Jco.2017.74.9598
Bhat AV, Palanichamy Kala M, Rao VK, et al. Epigenetic regulation of the PTEN-AKT-RAC1 axis by G9a is critical for tumor growth in alveolar rhabdomyosarcoma. Cancer Res. 2019;79(9):2232-2243. https://doi.org/10.1158/0008-5472.CAN-18-2676
Langdon CG, Gadek KE, Garcia MR, et al. Synthetic essentiality between PTEN and core dependency factor PAX7 dictates rhabdomyosarcoma identity. Nat Commun. 2021;12(1):5520. https://doi.org/10.1038/S41467-021-25829-4
Niemeyer BF, Parrish JK, Spoelstra NS, et al. Variable expression of PIK3R3 and PTEN in Ewing sarcoma impacts oncogenic phenotypes. Plos One. 2015;10(1):E0116895. https://doi.org/10.1371/Journal.Pone.0116895
Yu C, Zhang B, Li YL, et al. SIX1 reduces the expression of PTEN via activating PI3K/AKT signal to promote cell proliferation and tumorigenesis in osteosarcoma. Biomed Pharmacother. 2018;105:10-17. https://doi.org/10.1016/J.Biopha.2018.04.028
Zhou J, Xiao X, Wang W, et al. Association between PTEN and clinical-pathological features of osteosarcoma.
Biosci Rep. 2019;39(7):BSR20190954. https://doi.org/10.1042/Bsr20190954
Kelany M, Barth TF, Salem D, et al. Prevalence and prognostic implications of PD-L1 expression in soft tissue sarcomas. Pathol Oncol Res. 2021;27:1609804. https://doi.org/10.3389/Pore.2021.1609804
Kim JR, Moon YJ, Kwon KS, et al. Tumor infiltrating PD1-positive lymphocytes and the expression of PD-L1 predict poor prognosis of soft tissue sarcomas. Plos One. 2013;8(12):E82870. https://doi.org/10.1371/Journal. Pone.0082870
Orth MF, Buecklein VL, Kampmann E, et al. A comparative view on the expression patterns of PD-L1 and PD-1 in soft tissue sarcomas. Cancer Immunol Immunother. 2020;69(7):1353-1362. https://doi.org/10.1007/S00262- 020-02552-5
Vidotto T, Melo CM, Castelli E, et al. Emerging role of PTEN loss in evasion of the immune response to tumours.
Br J Cancer. 2020;122(12):1732-1743. https://doi.org/10.1038/S41416-020-0834-6
Stefano S, Giovanni S. The PTEN tumor suppressor gene in soft tissue sarcoma. Cancers (Basel). 2019;11(8):1169. https://doi.org/10.3390/Cancers11081169
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2023 Experimental Oncology
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
