LAG-3, TIM-3 and VISTA Expression on Tumor-Infiltrating Lymphocytes in Oropharyngeal Squamous Cell Carcinoma-Potential Biomarkers for Targeted Therapy Concepts

N. Wuerdemann*, K. Putz, H. Eckel, R. Jain, C. Wittekindt, C.U. Huebbers, S.J. Sharma, C. Langer, S. Gattenlohner, R. Buttner, E.J. Speel, M. Suchan, S. Wagner, A. Quaas, J.P. Klussmann

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


Tumor growth and survival requires a particularly effective immunosuppressant tumor microenvironment (TME) to escape destruction by the immune system. While immunosuppressive checkpoint markers like programmed cell death 1 ligand (PD-L1) are already being targeted in clinical practice, lymphocyte-activation-protein 3 (LAG-3), T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) and V-domain Ig suppressor of T cell activation (VISTA) inhibitors are currently under investigation in clinical trials. Reliable findings on the expression status of those immune checkpoint inhibitors on tumor-infiltrating lymphocytes (TILs) in the TME of oropharyngeal squamous cell carcinoma (OPSCC) are lacking. This work aims to describe the expression of LAG-3, TIM-3, and VISTA expression in the TME of OPSCC. We created a tissue microarray of paraffin-embedded tumor tissue of 241 OPSCC. Expression of the immune checkpoint protein LAG-3, TIM-3, and VISTA in OPSCC was evaluated using immunohistochemistry and results were correlated with CD8+ T-cell inflammation and human papillomavirus (HPV)-status. 73 OPSCC stained positive for LAG-3 (31%; HPV+:44%; HPV-:26%, p = 0.006), 122 OPSCC stained positive for TIM-3 (51%; HPV+:70%; HPV-:44%, p < 0.001) and 168 OPSCC (70%; HPV+:75%; HPV-:68%, p = 0.313) for VISTA. CD8+ T-cells were significantly associated with LAG-3, TIM-3 and VISTA expression (p < 0.001, p < 0.001, p = 0.007). Immune checkpoint therapy targeting LAG-3, TIM-3, and/or VISTA could be a promising treatment strategy especially in HPV-related OPSCC. Future clinical trials investigating the efficacy of a checkpoint blockade in consideration of LAG-3, TIM-3, and VISTA expression are required.
Original languageEnglish
Article number379
Number of pages15
JournalInternational Journal of Molecular Sciences
Issue number1
Publication statusPublished - 1 Jan 2021


  • cd8-positive t-lymphocytes
  • human papillomavirus
  • lag-3
  • oropharyngeal squamous cell carcinoma
  • tim-3
  • tumor microenvironment
  • vista
  • CD8-positive T-lymphocytes
  • LAG-3
  • TIM-3

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