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

Perea, FranciscoSánchez-Palencia, AbelGómez-Morales, MercedesBernal, MónicaConcha, ÁngelGarcía, Míguela MéndezGonzález-Ramírez, Amanda RocíoKerick, MartinMartin, JavierGarrido, FedericoRuiz-Cabello, FranciscoAptsiauri, Natalia2025-01-072025-01-072017-12-19https://hdl.handle.net/10668/25149Immune-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.enAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/HLA class I losslung cancerprogrammed death ligand 1 (PD-L1)tumor infiltrating lymphocytes (TILs)HLA class I loss and PD-L1 expression in lung cancer: impact on T-cell infiltration and immune escape.research article29423109open access10.18632/oncotarget.234691949-2553PMC5790526http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=download&path%5B%5D=23469&path%5B%5D=73924https://pmc.ncbi.nlm.nih.gov/articles/PMC5790526/pdf