Characteristics and impact of programmed death-ligand 1 expression, CD8+ tumor-infiltrating lymphocytes, and p16 status in head and neck squamous cell carcinoma
- 81 Downloads
No predictive biomarker of immune checkpoint inhibitors in head and neck squamous cell carcinoma (HNSCC) has been well established. The impact of programmed death-ligand 1 (PD-L1) expression, CD8+ tumor-infiltrating lymphocytes (TILs), and p16 status in HNSCC is unclear and may vary according to ethnicity.
HNSCC patients treated between 2007 and 2013 were reviewed. Archival tissues were retrieved for PD-L1, CD8+ TILs, and p16 analyses. PD-L1 expression was evaluated by using the validated SP142 assay on the VENTANA platform. CD8+ TILs were defined by using semiquantitative scoring.
A total of 203 patients were analyzed. PD-L1 expression was observed in 80% of patients and was significantly associated with older age (P < 0.001). A high CD8+ TIL score (≥ 6) was significantly associated with never-smoking (P = 0.020), oral cavity cancer (P < 0.001), and stage M0 at presentation (P = 0.025). The p16 status was positive in 12% of patients. Patients with a high TIL score had a significantly longer OS (P = 0.032). Patients with PD-L1 expression of 1–49% and ≥ 50% were associated with a significantly shorter OS compared with those with PD-L1 < 1% (P = 0.027 and P = 0.011, respectively). Multivariate analysis showed that PD-L1 ≥ 50% was significantly associated with a poor OS. (HR 2.98 [95% CI 1.2–7.39]; P = 0.019.)
A high prevalence of PD-L1 expression was observed in HNSCC using the validated SP142 assay. PD-L1 expression was associated with older age, while highly PD-L1 expression (≥ 50%) was an independent prognostic factor for poor OS in anti-PD1/PD-L1 untreated HNSCC patients.
KeywordsProgrammed death ligand-1 CD8+ tumor infiltrating lymphocytes P16 Human papillomavirus Head and neck squamous cell carcinoma
This work was supported by a grant from the Ramathibodi Cancer Center Grant. N. Ngamphaiboon received funding from the Research University Network (RUN), and the Thailand Research Fund (TRF), and the Research Development Grant from the Ramathibodi Hospital. The authors thank Ms. Dollapas Punpanich for statistical analysis.
Compliance with ethical standards
Conflict of interest
All authors declare no conflict of interest.
The Ramathibodi Ethic Committee approved a waiver of consent for this study as a retrospective chart review. Archrival tissues used in this study were considered as a leftover specimen. The research involves no more than minimal risk to the subject and is not adversely affect the rights and welfare of the subjects. All patient identifications were protected according to the GCP guideline and not published in the manuscript. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
- 4.Seiwert TY, Burtness B, Mehra R, Weiss J, Berger R, Eder JP, et al. Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial. Lancet Oncol. 2016;17(7):956–65. https://doi.org/10.1016/S1470-2045(16)30066-3.CrossRefPubMedGoogle Scholar
- 5.Chow LQM, Haddad R, Gupta S, Mahipal A, Mehra R, Tahara M, et al. Antitumor activity of pembrolizumab in biomarker-unselected patients with recurrent and/or metastatic head and neck squamous cell carcinoma: results from the phase Ib KEYNOTE-012 expansion cohort. J Clin Oncol. 2016;34(32):3838–45. https://doi.org/10.1200/JCO.2016.68.1478.CrossRefPubMedGoogle Scholar
- 7.Bauml J, Seiwert TY, Pfister DG, Worden F, Liu SV, Gilbert J, et al. Pembrolizumab for platinum- and cetuximab-refractory head and neck cancer: results from a single-arm, phase II study. J Clin Oncol. 2017;35(14):1542–9. https://doi.org/10.1200/JCO.2016.70.1524.CrossRefPubMedPubMedCentralGoogle Scholar
- 8.Ferris R, Blumenschein G Jr, Fayette J, Guigay J, Colevas AD, Licitra L, et al. Nivolumab vs investigator’s choice in recurrent or metastatic squamous cell carcinoma of the head and neck: 2-year long-term survival update of CheckMate 141 with analyses by tumor PD-L1 expression. Oral Oncol. 2018;81:45–51.CrossRefGoogle Scholar
- 15.Balermpas P, Rodel F, Rodel C, Krause M, Linge A, Lohaus F, et al. CD8+ tumour-infiltrating lymphocytes in relation to HPV status and clinical outcome in patients with head and neck cancer after postoperative chemoradiotherapy: a multicentre study of the German cancer consortium radiation oncology group (DKTK-ROG). Int J Cancer. 2016;138(1):171–81. https://doi.org/10.1002/ijc.29683.CrossRefPubMedGoogle Scholar
- 18.De Meulenaere A, Vermassen T, Aspeslagh S, Deron P, Duprez F, Laukens D, et al. Tumor PD-L1 status and CD8(+) tumor-infiltrating T cells: markers of improved prognosis in oropharyngeal cancer. Oncotarget. 2017;8(46):80443–52. https://doi.org/10.18632/oncotarget.19045.CrossRefPubMedPubMedCentralGoogle Scholar
- 20.Soulieres D, Cohen EE, Le Tourneau C, Dinis J, Licitra L, Ahn MJ, et al. Updated survival results of the KEYNOTE-040 study of pembrolizumab vs standard-of-care chemotherapy for recurrent or metastatic head and neck squamous cell carcinoma. In: AACR; Chicago, IL; 2018.Google Scholar
- 21.Segal NH, Ou SHI, Balmanoukian AS, Massarelli E, Brahmer JR, Weiss J, et al. Updated safety and efficacy of durvalumab (MEDI4736), an anti-PD-L 1 antibody, in patients from a squamous cell carcinoma of the head and neck (SCCHN) expansion cohort. Ann Oncol. 2016. https://doi.org/10.1093/annonc/mdw376.1.CrossRefGoogle Scholar
- 23.Ono T, Azuma K, Kawahara A, Sasada T, Hattori S, Sato F, et al. Association between PD-L1 expression combined with tumor-infiltrating lymphocytes and the prognosis of patients with advanced hypopharyngeal squamous cell carcinoma. Oncotarget. 2017;8(54):92699–714. https://doi.org/10.18632/oncotarget.21564.CrossRefPubMedPubMedCentralGoogle Scholar
- 24.Oguejiofor K, Galletta-Williams H, Dovedi SJ, Roberts DL, Stern PL, West CM. Distinct patterns of infiltrating CD8+ T cells in HPV+ and CD68 macrophages in HPV− oropharyngeal squamous cell carcinomas are associated with better clinical outcome but PD-L1 expression is not prognostic. Oncotarget. 2017;8(9):14416–27. https://doi.org/10.18632/oncotarget.14796.CrossRefPubMedPubMedCentralGoogle Scholar
- 26.Hirsch FR, McElhinny A, Stanforth D, Ranger-Moore J, Jansson M, Kulangara K, et al. PD-L1 immunohistochemistry assays for lung cancer: results from phase 1 of the blueprint PD-L1 IHC assay comparison project. J Thorac Oncol. 2017;12(2):208–22. https://doi.org/10.1016/j.jtho.2016.11.2228.CrossRefPubMedGoogle Scholar
- 27.Rimm DL, Han G, Taube JM, Yi ES, Bridge JA, Flieder DB, et al. A prospective multi-institutional, pathologist-based assessment of 4 immunohistochemistry assays for PD-L1 expression in non-small cell lung cancer. JAMA Oncol. 2017;3(8):1051–8. https://doi.org/10.1001/jamaoncol.2017.0013.CrossRefPubMedPubMedCentralGoogle Scholar
- 28.Badoual C, Hans S, Merillon N, Van Ryswick C, Ravel P, Benhamouda N, et al. PD-1-expressing tumor-infiltrating T cells are a favorable prognostic biomarker in HPV-associated head and neck cancer. Cancer Res. 2013;73(1):128–38. https://doi.org/10.1158/0008-5472.CAN-12-2606.CrossRefPubMedGoogle Scholar
- 30.Hendry S, Salgado R, Gevaert T, Russell PA, John T, Thapa B, et al. Assessing tumor-infiltrating lymphocytes in solid tumors: a practical review for pathologists and proposal for a standardized method from the international immuno-oncology biomarkers working group: part 2: TILs in melanoma, gastrointestinal tract carcinomas, non-small cell lung carcinoma and mesothelioma, endometrial and ovarian carcinomas, squamous cell carcinoma of the head and neck, genitourinary carcinomas, and primary brain tumors. Adv Anat Pathol. 2017;24(6):311–35. https://doi.org/10.1097/PAP.0000000000000161.CrossRefPubMedPubMedCentralGoogle Scholar
- 32.Phusingha P, Ekalaksananan T, Vatanasapt P, Loyha K, Promthet S, Kongyingyoes B, et al. Human papillomavirus (HPV) infection in a case-control study of oral squamous cell carcinoma and its increasing trend in northeastern Thailand. J Med Virol. 2017;89(6):1096–101. https://doi.org/10.1002/jmv.24744.CrossRefPubMedGoogle Scholar