Prognostic value of tumor-infiltrating immune cells and immune checkpoints in elderly head-and-neck squamous cell carcinoma patients undergoing definitive (chemo)radiotherapy

Abstract

Background and purpose: Tumor-infiltrating lymphocytes (TILs) are associated with locoregional control (LRC) in head-and-neck squamous cell carcinoma (HNSCC) patients undergoing (chemo)radiotherapy. As immunosenescence results in reduced immune activity, the role of TILs in elderly HNSCC patients may differ compared to younger patients, providing a rationale to study the prognostic role of TILs and immune checkpoints (ICs) in this population. Material and methods: Sixty-three HNSCC patients aged ≥ 65 years undergoing definitive (chemo)radiotherapy between 2010 and 2019 with sufficient material from pre-treatment biopsies were included in the analysis. Immunohistochemical stainings of CD3, CD4, CD8, PD-L1, TIM3, LAG3, TIGIT and CD96, and of osteopontin as an immunosenescence-associated protein were performed. Overall survival (OS) and progression-free survival (PFS) were determined using the Kaplan–Meier method, and Fine-Gray's models were used for locoregional failure (LRF) analyses. Results: While there was no correlation between patient age and IC expression, osteopontin levels correlated with increasing age (r = 0.322, p < 0.05). Two-year OS, PFS, and LRC were 44%, 34%, and 71%, respectively. Increased LAG3 expression, both intraepithelial (SHR = 0.33, p < 0.05) and stromal (SHR = 0.38, p < 0.05), and elevated stromal TIM3 expression (SHR = 0.32, p < 0.05) corresponded with reduced LRFs. Absent tumoral PD-L1 expression (TPS = 0%) was associated with more LRFs (SHR = 0.28, p < 0.05). There was a trend towards improved LRF rates in elderly patients with increased intraepithelial CD3 + (SHR = 0.52, p = 0.07) and CD8 + (SHR = 0.52, p = 0.09) TIL levels. Conclusion: LAG3, TIM3 and TPS are promising biomarkers in elderly HNSCC patients receiving (chemo)radiotherapy. Considering the frequency of non-cancer related deaths in this population, the prognostic value of these biomarkers primarily relates to LRC.