Lymphocyte activation gene 3 (LAG3) protein expression on tumor-infiltrating lymphocytes in aggressive and TP53-mutated salivary gland carcinomas

Cancer Immunol Immunother. 2020 Jul;69(7):1363-1373. doi: 10.1007/s00262-020-02551-6. Epub 2020 Mar 30.

Abstract

Salivary gland carcinomas (SGCs) are rare and can be subdivided into distinct entities, some of which confer a poor prognosis. As targets for effective systemic therapy are warranted, some studies investigated the role of immune-checkpoint proteins PD-L1 and CTLA-4 in SGC. Our study depicts the expression of lymphocyte activation gene 3 (LAG3) in a test cohort and a larger validation cohort, totaling 139 SGCs. LAG3 is expressed on tumor-infiltrating lymphocytes (TILs), mediates T cell exhaustion and is subject to numerous currently recruiting clinical studies. Overall, one-third of SGCs were infiltrated by LAG3-expressing TILs with a strikingly high concordance between the test cohort and the validation cohort (30% and 28.2%, respectively). In the validation cohort, entity-wise LAG3 expression frequencies were highly variable. The highest rates were observed in salivary duct carcinoma (SDC; 66.7%) and adenocarcinoma not otherwise specified (ANOS; 50.0%). We observed LAG3 expression on effector T cells and in smaller frequencies also on FOXP3- T helper cells and FOXP3+ Tregs. LAG3 expression significantly correlated with advanced nodal metastases, cytotoxic T cell infiltrate and TP53 mutations. In the group of adenoid cystic carcinomas, LAG3 expression was also associated with a shorter event-free survival (EFS). Tumors with TP53 nonsense mutations (TP53 null type) exhibited higher LAG3 frequencies and a shorter EFS compared to TP53 wild type. This is the first report of LAG3 expression in SGC, a promising target for immunotherapy. LAG3 blockage could be distinctly applicable for SDC and ANOS, two SGC types with a particularly poor outcome.

Keywords: LAG3; Prognosis; Salivary gland carcinoma; TP53; Tumor micro-environment.

MeSH terms

  • Aged
  • Antigens, CD / metabolism*
  • Biomarkers, Tumor / analysis*
  • CD8 Antigens / metabolism*
  • Combined Modality Therapy
  • Female
  • Follow-Up Studies
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lymphocytes, Tumor-Infiltrating / immunology*
  • Male
  • Mutation*
  • Prognosis
  • Retrospective Studies
  • Salivary Gland Neoplasms / genetics
  • Salivary Gland Neoplasms / immunology
  • Salivary Gland Neoplasms / metabolism
  • Salivary Gland Neoplasms / pathology*
  • Survival Rate
  • Tumor Suppressor Protein p53 / genetics*

Substances

  • Antigens, CD
  • Biomarkers, Tumor
  • CD223 antigen
  • CD8 Antigens
  • TP53 protein, human
  • Tumor Suppressor Protein p53