HLA class I loss and PD-L1 expression in lung cancer: impact on T-cell infiltration and immune escape

Open Access

Abstract

Immune-checkpoint inhibitors show encouraging results in cancer treatment, but the clinical benefit is limited exclusively to a subset of patients. We analyzed the density and composition of tumor T-cell infiltration in non-small-cell lung carcinoma (NSCLC) in relation to PD-L1 and HLA class I (HLA-I) expression. We found that positive HLA-I expression, independently on PD-L1 status, is the key factor determining the increased density of the immune infiltrate. When both markers were analyzed simultaneously, we identified four phenotypes of HLA-I and PD-L1 co-expression. They demonstrated different patterns of tumor infiltration and clinicopathologic characteristics, including the tumor size and lymphatic spread. All HLA-I+/PD-L1+ tumors had a high degree of intratumoral infiltration with CD8+T-lymphocytes, whereas HLA-I loss was associated with a significantly reduced number of tumor infiltrating T-lymphocytes mostly restrained in the stroma surrounding the tumor nest. HLA-I-negative/PD-L1-positive tumors had bigger size (T) and lower grade of infiltration with CD8+T-cells. It represents a cancer immune escape phenotype that combines two independent mechanisms of immune evasion: loss of HLA-I and upregulation of PD-L1. Using GCH-array analysis of human lung cancer cell lines we found that the loss of heterozygosity (LOH) with complete or partial deletion of HLA-I genes is the principal mechanism of HLA-I alterations. This irreversible defect, which could potentially decrease the clinical efficacy of lung cancer immunotherapy, appears to be underestimated. In conclusion, our results suggest that the analysis of HLA-I is very important for the selection of potential responders to cancer immunotherapy. ; This work was supported by the grants from Spanish Institute of Heath Carlos III (ISCIII, Instituto Carlos III) co-financed by European Union (FEDER-Fondo Europeo de Desarrollo Regional) (PI12/02031, PI08/1265, PI11/01022, PI11/01386, RETIC RD 06/020, RD09/0076/00165, PT13/0010/0039, PI14/01978, PI16/00752) and by the Junta de Andalucía in Spain (Groups CTS-143, CTS-695,CTS-3952, CVI-4740, PI 09/0382 grant). This study is part of the doctoral thesis of Francisco Perea and his pre-doctoral fellowship was partially financed by Becton Dickinson and Beckman Coulter. ; Peer reviewed