The positive prognostic effect of stromal CD8+ tumor-infiltrating T cells is restrained by the expression of HLA-E in non-small cell lung carcinoma

INTRODUCTION: Tumor-infiltrating CD8+ T cells are associated with improved clinical outcomes in non-small cell lung cancer (NSCLC). Here we studied their prognostic effect in the context of the expression of HLA molecules that are key in tumor recognition (HLA-A, B and C) or suppression of immunity (HLA-E) as this is still unknown. METHODS: Tumor tissue of 197 patients with resected pulmonary adenocarcinoma was analyzed for the presence of CD8+ T cells and the expression of β2-microglobulin, HLA-A, HLA-B/C and HLA-E. The relation of these parameters with overall survival (OS) was assessed. RESULTS: Loss and low expression of HLA-A or HLA-B/C was found in 44% and 75% of cases respectively. A high CD8+ tumor infiltration was strongly associated with clinical benefit only when the tumors retained good expression of HLA-A and HLA-B/C (p=0.004). In addition, more than 70% of the tumors were found to display a high expression of HLA-E. The expression of HLA-E by tumor cells was an independent negative prognostic factor for OS (p=0.031). Importantly, a dense stromal CD8+ T cell infiltration was strongly associated with improved OS only in HLA-E negative tumors (p=0.005) and its prognostic effect was completely abolished when tumors highly expressed HLA-E (p=0.989). CONCLUSIONS: CD8+ T cell infiltration strongly contributes to a better prognosis in NSCLC when the tumor cells retain the expression of classical HLA class I and do not express HLA-E. Therefore, analysis of HLA-A, -B/C and HLA-E expression should be included as biomarkers to predict the response to immunotherapy.