Abstract
Background
PD-L1 and VISTA are thought to play a role in escape from the immune system, tumor progression, and treatment response in tumoral tissue. The current study aimed to evaluate the effects of radiotherapy (RT) and chemoradiotherapy (CRT) on PD-L1 and VISTA expression in head and neck cancers.
Methods
PD-L1 and VISTA expression were compared between the primary biopsy taken at the time of diagnosis and refractory tissue biopsies of patients who received definitive CRT or recurrent tissue biopsies of patients who had surgery followed by adjuvant RT or CRT.
Results
In total, 47 patients were included. Radiotherapy had no effect on the expression levels of PD-L1 and VISTA in patients with head and neck cancer (p = 0.542 and p = 0.425, respectively). A positive correlation was found between PD-L1 and VISTA expression (p < 0.001; r = 0.560). PD-L1 and VISTA expression in the first biopsy were found to be significantly higher in clinical lymph node-positive patients compared to node-negative patients (PD-L1 p = 0.038; VISTA p = 0.018). The median overall survival of patients with ≥ 1% VISTA expression in the initial biopsy was significantly shorter than that of patients with < 1% VISTA expression (52.4 vs. 110.1 months, respectively; p = 0.048).
Conclusion
It was found that PD-L1 and VISTA expression did not change with RT or CRT. Further studies are needed to evaluate the relationship of PD-L1 and VISTA expression with RT and CRT.
Similar content being viewed by others
References
Siegel RL, Miller KD, Fuchs HE, Jemal A (2021) Cancer statistics, 2021. CA Cancer J Clin 71(1):7–33. https://doi.org/10.3322/caac.21654
Cohen EEW, Bell RB, Bifulco CB, Burtness B, Gillison ML, Harrington KJ et al (2019) The society for immunotherapy of cancer consensus statement on immunotherapy for the treatment of squamous cell carcinoma of the head and neck (HNSCC). J Immunother Cancer 7(1):184. https://doi.org/10.1186/s40425-019-0662-5
Cognetti DM, Weber RS, Lai SY (2008) Head and neck cancer: an evolving treatment paradigm. Cancer 113(7):1911–1932. https://doi.org/10.1002/cncr.23654
Havel JJ, Chowell D, Chan TA (2019) The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy. Nat Rev Cancer 19(3):133–150. https://doi.org/10.1038/s41568-019-0116-x
Gibney GT, Weiner LM, Atkins MB (2016) Predictive biomarkers for checkpoint inhibitor-based immunotherapy. Lancet Oncol 17(12):e542–e51. https://doi.org/10.1016/s1470-2045(16)30406-5
Maleki Vareki S, Garrigós C, Duran I (2017) Biomarkers of response to PD-1/PD-L1 inhibition. Crit Rev Oncol Hematol 116:116–124. https://doi.org/10.1016/j.critrevonc.2017.06.001
Cramer JD, Burtness B, Ferris RL (2019) Immunotherapy for head and neck cancer: recent advances and future directions. Oral Oncol 99:104460. https://doi.org/10.1016/j.oraloncology.2019.104460
Nowak EC, Lines JL, Varn FS, Deng J, Sarde A, Mabaera R et al (2017) Immunoregulatory functions of VISTA. Immunol Rev 276(1):66–79. https://doi.org/10.1111/imr.12525
Zou W, Chen L (2008) Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev Immunol 8(6):467–477. https://doi.org/10.1038/nri2326
Tagliamento M, Bironzo P, Novello S (2020) New emerging targets in cancer immunotherapy: the role of VISTA. ESMO Open 4(3):e683. https://doi.org/10.1136/esmoopen-2020-000683
Huang X, Zhang X, Li E, Zhang G, Wang X, Tang T et al (2020) VISTA: an immune regulatory protein checking tumor and immune cells in cancer immunotherapy. J Hematol Oncol 13(1):83. https://doi.org/10.1186/s13045-020-00917-y
Zhu AX, Finn RS, Ikeda M, Sung MW, Baron AD, Kudo M et al (2020) A phase Ib study of lenvatinib (LEN) plus pembrolizumab (PEMBRO) in unresectable hepatocellular carcinoma (uHCC). American Society of Clinical Oncology
Makowska A, Meier S, Shen L, Busson P, Baloche V, Kontny U (2021) Anti-PD‑1 antibody increases NK cell cytotoxicity towards nasopharyngeal carcinoma cells in the context of chemotherapy-induced upregulation of PD‑1 and PD-L1. Cancer Immunol Immunother 70(2):323–336. https://doi.org/10.1007/s00262-020-02681-x
Tran L, Allen CT, Xiao R, Moore E, Davis R, Park SJ et al (2017) Cisplatin alters antitumor immunity and synergizes with PD-1/PD-L1 inhibition in head and neck squamous cell carcinoma. Cancer Immunol Res 5(12):1141–1151. https://doi.org/10.1158/2326-6066.Cir-17-0235
Demaria S, Golden EB, Formenti SC (2015) Role of local radiation therapy in cancer immunotherapy. JAMA Oncol 1(9):1325–1332. https://doi.org/10.1001/jamaoncol.2015.2756
Dewan MZ, Galloway AE, Kawashima N, Dewyngaert JK, Babb JS, Formenti SC et al (2009) Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA‑4 antibody. Clin Cancer Res 15(17):5379–5388. https://doi.org/10.1158/1078-0432.Ccr-09-0265
Buchwald ZS, Wynne J, Nasti TH, Zhu S, Mourad WF, Yan W et al (2018) Radiation, immune checkpoint blockade and the abscopal effect: a critical review on timing, dose and fractionation. Front Oncol 8:612. https://doi.org/10.3389/fonc.2018.00612
Ferris RL, Blumenschein G, Fayette J, Guigay J, Colevas AD, Licitra L et al (2016) Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med 375(19):1856–1867. https://doi.org/10.1056/NEJMoa1602252
Cohen EEW, Soulières D, Le Tourneau C, Dinis J, Licitra L, Ahn MJ et al (2019) Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study. Lancet 393(10167):156–167. https://doi.org/10.1016/s0140-6736(18)31999-8
Bahleda R, Braiteh F, Balmanoukian A, Braña I, Hodi F, Garbo L et al (2017) Long-term safety and clinical outcomes of atezolizumab in head and neck cancer: phase Ia trial results. Ann Oncol 28:v373
Katsuya Y, Horinouchi H, Asao T, Kitahara S, Goto Y, Kanda S et al (2016) Expression of programmed death 1 (PD-1) and its ligand (PD-L1) in thymic epithelial tumors: Impact on treatment efficacy and alteration in expression after chemotherapy. Lung Cancer 99:4–10. https://doi.org/10.1016/j.lungcan.2016.05.007
Pilones KA, Hensler M, Daviaud C, Kraynak J, Fucikova J, Galluzzi L et al (2020) Converging focal radiation and immunotherapy in a preclinical model of triple negative breast cancer: contribution of VISTA blockade. OncoImmunology 9(1):1830524. https://doi.org/10.1080/2162402x.2020.1830524
van den Ende T, van den Boorn HG, Hoonhout NM, van Etten-Jamaludin FS, Meijer SL, Derks S et al (2020) Priming the tumor immune microenvironment with chemo(radio)therapy: a systematic review across tumor types. Biochim Biophys Acta Rev Cancer 1874(1):188386. https://doi.org/10.1016/j.bbcan.2020.188386
Gong J, Le TQ, Massarelli E, Hendifar AE, Tuli R (2018) Radiation therapy and PD-1/PD-L1 blockade: the clinical development of an evolving anticancer combination. J Immunother Cancer 6(1):46. https://doi.org/10.1186/s40425-018-0361-7
Wang Y, Kim TH, Fouladdel S, Zhang Z, Soni P, Qin A et al (2019) PD-L1 expression in circulating tumor cells increases during radio(chemo)therapy and indicates poor prognosis in non-small cell lung cancer. Sci Rep 9(1):566. https://doi.org/10.1038/s41598-018-36096-7
Oweida A, Lennon S, Calame D, Korpela S, Bhatia S, Sharma J et al (2017) Ionizing radiation sensitizes tumors to PD-L1 immune checkpoint blockade in orthotopic murine head and neck squamous cell carcinoma. OncoImmunology 6(10):e1356153. https://doi.org/10.1080/2162402x.2017.1356153
Hecht M, Büttner-Herold M, Erlenbach-Wünsch K, Haderlein M, Croner R, Grützmann R et al (2016) PD-L1 is upregulated by radiochemotherapy in rectal adenocarcinoma patients and associated with a favourable prognosis. Eur J Cancer 65:52–60. https://doi.org/10.1016/j.ejca .2016.06.015
Patel KR, Martinez A, Stahl JM, Logan SJ, Perricone AJ, Ferris MJ et al (2018) Increase in PD-L1 expression after pre-operative radiotherapy for soft tissue sarcoma. OncoImmunology 7(7):e1442168
Yoneda K, Kuwata T, Kanayama M, Mori M, Kawanami T, Yatera K et al (2019) Alteration in tumoural PD-L1 expression and stromal CD8-positive tumour-infiltrating lymphocytes after concurrent chemo-radiotherapy for non-small cell lung cancer. Br J Cancer 121(6):490–496. https://doi.org/10.1038/s41416-019-0541-3
Qian JM, Schoenfeld JD (2020) Radiotherapy and immunotherapy for head and neck cancer: current evidence and challenges. Front Oncol 10:608772. https://doi.org/10.3389/fonc.2020.608772
Schoop H, Bregenzer A, Halske C, Behrens HM, Krüger S, Egberts JH et al (2020) Therapy resistance in neoadjuvantly treated gastric cancer and cancer of the gastroesophageal junction is associated with an increased expression of immune checkpoint inhibitors-comparison against a therapy naïve cohort. Transl Oncol 13(2):165–176. https://doi.org/10.1016/j.tranon.2019.11.004
McBride S, Sherman E, Tsai CJ, Baxi S, Aghalar J, Eng J et al (2021) Randomized phase II trial of nivolumab with stereotactic body radiotherapy versus nivolumab alone in metastatic head and neck squamous cell carcinoma. J Clin Oncol 39(1):30–37. https://doi.org/10.1200/jco.20.00290
Theelen W, Peulen HMU, Lalezari F, van der Noort V, de Vries JF, Aerts J et al (2019) Effect of pembrolizumab after stereotactic body radiotherapy vs pembrolizumab alone on tumor response in patients with advanced non-small cell lung cancer: results of the PEMBRO-RT phase 2 randomized clinical trial. JAMA Oncol 5(9):1276–1282. https://doi.org/10.1001/jamaoncol.2019.1478
Patel SP, Kurzrock R (2015) PD-L1 expression as a predictive biomarker in cancer immunotherapy. Mol Cancer Ther 14(4):847–856. https://doi.org/10.1158/1535-7163.Mct-14-0983
Downes MR, Slodkowska E, Katabi N, Jungbluth AA, Xu B (2020) Inter- and intraobserver agreement of programmed death ligand 1 scoring in head and neck squamous cell carcinoma, urothelial carcinoma and breast carcinoma. Histopathology 76(2):191–200. https://doi.org/10.1111/his.13946
Rasmussen JH, Lelkaitis G, Håkansson K, Vogelius IR, Johannesen HH, Fischer BM et al (2019) Intratumor heterogeneity of PD-L1 expression in head and neck squamous cell carcinoma. Br J Cancer 120(10):1003–1006. https://doi.org/10.1038/s41416-019-0449-y
Burtness B, Harrington KJ, Greil R, Soulières D, Tahara M, de Castro G Jr. et al (2019) Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet 394(10212):1915–1928. https://doi.org/10.1016/s0140-6736(19)32591-7
Liu J, Yuan Y, Chen W, Putra J, Suriawinata AA, Schenk AD et al (2015) Immune-checkpoint proteins VISTA and PD‑1 nonredundantly regulate murine T‑cell responses. Proc Natl Acad Sci U S A 112(21):6682–6687. https://doi.org/10.1073/pnas.1420370112
Kakavand H, Jackett LA, Menzies AM, Gide TN, Carlino MS, Saw RPM et al (2017) Negative immune checkpoint regulation by VISTA: a mechanism of acquired resistance to anti-PD‑1 therapy in metastatic melanoma patients. Mod Pathol 30(12):1666–1676. https://doi.org/10.1038/modpathol.2017.89
Wu L, Deng WW, Huang CF, Bu LL, Yu GT, Mao L et al (2017) Expression of VISTA correlated with immunosuppression and synergized with CD8 to predict survival in human oral squamous cell carcinoma. Cancer Immunol Immunother 66(5):627–636. https://doi.org/10.1007/s00262-017-1968-0
Zhang M, Pang H‑J, Zhao W, Li Y‑F, Yan L‑X, Dong Z‑Y et al (2018) VISTA expression associated with CD8 confers a favorable immune microenvironment and better overall survival in hepatocellular carcinoma. BMC Cancer 18(1):1–8
Zong L, Zhou Y, Zhang M, Chen J, Xiang Y (2020) VISTA expression is associated with a favorable prognosis in patients with high-grade serous ovarian cancer. Cancer Immunol Immunother 69(1):33–42. https://doi.org/10.1007/s00262-019-02434-5
Cao X, Ren X, Zhou Y, Mao F, Lin Y, Wu H et al (2020) VISTA expression on immune cells correlates with favorable prognosis in patients with triple-negative breast cancer. Front Oncol 10:583966. https://doi.org/10.3389/fonc.2020.583966
Vassilakopoulou M, Avgeris M, Velcheti V, Kotoula V, Rampias T, Chatzopoulos K et al (2016) Evaluation of PD-L1 expression and associated tumor-infiltrating lymphocytes in laryngeal squamous cell carcinoma. Clin Cancer Res 22(3):704–713. https://doi.org/10.1158/1078-0432.Ccr-15-1543
Lin YM, Sung WW, Hsieh MJ, Tsai SC, Lai HW, Yang SM et al (2015) High PD-L1 expression correlates with metastasis and poor prognosis in oral squamous cell carcinoma. PLoS ONE 10(11):e142656. https://doi.org/10.1371/journal.pone.0142656
Liao H, Zhu H, Liu S, Wang H (2018) Expression of V‑domain immunoglobulin suppressor of T cell activation is associated with the advanced stage and presence of lymph node metastasis in ovarian cancer. Oncol Lett 16(3):3465–3472. https://doi.org/10.3892/ol.2018.9059
Yang WF, Wong MCM, Thomson PJ, Li KY, Su YX (2018) The prognostic role of PD-L1 expression for survival in head and neck squamous cell carcinoma: a systematic review and meta-analysis. Oral Oncol 86:81–90. https://doi.org/10.1016/j.oraloncology.2018.09.016
Tang H, Zhou X, Ye Y, Zhou Y, Wu C, Xu Y (2020) The different role of PD-L1 in head and neck squamous cell carcinomas: a meta-analysis. Pathol Res Pract 216(1):152768. https://doi.org/10.1016/j.prp.2019.152768
Bauml J, Seiwert TY, Pfister DG, Worden F, Liu SV, Gilbert J et al (2017) Pembrolizumab for platinum- and cetuximab-refractory head and neck cancer: results from a single-arm, phase II study. J Clin Oncol 35(14):1542–1549. https://doi.org/10.1200/jco.2016.70.1524
Ferris RL, Blumenschein G Jr., Fayette J, Guigay J, Colevas AD, Licitra L et al (2016) Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med 375(19):1856–1867. https://doi.org/10.1056/NEJMoa1602252
Mehra R, Seiwert TY, Gupta S, Weiss J, Gluck I, Eder JP et al (2018) Efficacy and safety of pembrolizumab in recurrent/metastatic head and neck squamous cell carcinoma: pooled analyses after long-term follow-up in KEYNOTE-012. Br J Cancer 119(2):153–159. https://doi.org/10.1038/s41416-018-0131-9
Aydil U, Akmansu M, Gümüşay Ö, Eravcı FC, Bakkal FK, Yazıcı Ö et al (2019) Failure of concurrent chemoradiotherapy for organ preservation in laryngeal cancer: survival outcomes and recurrence patterns. Ear Nose Throat J 98(7):E92–e6. https://doi.org/10.1177/0145561319839788
Agra IM, Ferlito A, Takes RP, Silver CE, Olsen KD, Stoeckli SJ et al (2012) Diagnosis and treatment of recurrent laryngeal cancer following initial nonsurgical therapy. Head Neck 34(5):727–735. https://doi.org/10.1002/hed.21739
Esteller E, Vega MC, López M, Quer M, León X (2011) Salvage surgery after locoregional failure in head and neck carcinoma patients treated with chemoradiotherapy. Eur Arch Otorhinolaryngol 268(2):295–301. https://doi.org/10.1007/s00405-010-1365-1
León X, Quer M, Orús C, López M, Gras JR, Vega M (2001) Results of salvage surgery for local or regional recurrence after larynx preservation with induction chemotherapy and radiotherapy. Head Neck 23(9):733–738. https://doi.org/10.1002/hed.1104
Birkeland AC, Beesley L, Bellile E, Rosko AJ, Hoesli R, Chinn SB et al (2017) Predictors of survival after total laryngectomy for recurrent/persistent laryngeal squamous cell carcinoma. Head Neck 39(12):2512–2518. https://doi.org/10.1002/hed.24918
Acknowledgements
This study was supported by the Gazi University Projects of Scientific Investigation.
Funding
The authors received no specific funding for this work. This study was carried out as part of the Project Support program of the Gazi University Projects of Scientific Investigation.
Author information
Authors and Affiliations
Contributions
All authors contributed to study conception and design. Material preparation, data collection, and analysis were performed by Görkem Yazıcı Şener, Osman Sütcüoğlu, Betül Öğüt, Nalan Akyürek, and Ozan Yazıcı. The first draft of the manuscript was written by Osman Sütcüoğlu, Görkem Yazıcı Şener, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Corresponding author
Ethics declarations
Conflict of interest
G.Y. Şener, O. Sütcüoğlu, B. Öğüt, D.C. Güven, A. Kavuncuoğlu, N. Özdemir, A. Özet, S. Aksoy, Y.G.G. Tezel, N. Akyürek, and O. Yazıcı declare that they have no competing interests.
Ethical standards
Ethical approval was waived by the Ethics Committee of Gazi University in view of the retrospective nature of the study and all the procedures performed were part of the routine care.
Additional information
Availability of data and material
The datasets generated during and/or analyzed in the current study are available from the corresponding author upon reasonable request.
Appendix
Appendix
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Şener, G.Y., Sütcüoğlu, O., Öğüt, B. et al. Comparison of PD-L1 and VISTA expression status in primary and recurrent/refractory tissue after (chemo)radiotherapy in head and neck cancer. Strahlenther Onkol 199, 761–772 (2023). https://doi.org/10.1007/s00066-023-02053-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00066-023-02053-1