Research Papers:

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

Francisco Perea, Abel Sánchez-Palencia, Mercedes Gómez-Morales, Mónica Bernal, Ángel Concha, Míguela Méndez García, Amanda Rocío González-Ramírez, Martin Kerick, Javier Martin, Federico Garrido, Francisco Ruiz-Cabello _ and Natalia Aptsiauri

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Oncotarget. 2018; 9:4120-4133. https://doi.org/10.18632/oncotarget.23469

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Francisco Perea1, Abel Sánchez-Palencia2, Mercedes Gómez-Morales3, Mónica Bernal1, Ángel Concha4, Míguela Méndez García1, Amanda Rocío González-Ramírez5,7, Martin Kerick6, Javier Martin6, Federico Garrido1,7,8, Francisco Ruiz-Cabello1,7,8 and Natalia Aptsiauri1,7,8

1Servicio de Análisis Clínicos e Inmunología, UGC Laboratorio Clínico, Hospital Universitario Virgen de las Nieves, Granada, Spain

2Servicio de Cirugía Torácica, Hospital Universitario Virgen de las Nieves, Granada, Spain

3Departamento de Anatomía Patológica, Universidad de Granada, Granada, Spain

4Servicio de Anatomía Patológica y Biobanco, Complejo Hospitalario Universitario, La Coruña, Spain

5Fundación de Investigación Biosanitaria Alejandro Otero, FIBAO, Granada, Spain

6Instituto de Parasitología y Biomedicina López Neyra, CSIC, Granada, Spain

7Instituto de Investigación Biosanitaria ibs.Granada, Granada, Spain

8Departamento de Bioquímica, Biología Molecular e Inmunología III, Universidad de Granada, Granada, Spain

Correspondence to:

Francisco Ruiz-Cabello, email: [email protected]

Keywords: lung cancer; HLA class I loss; programmed death ligand 1 (PD-L1); tumor infiltrating lymphocytes (TILs)

Received: October 30, 2017     Accepted: November 26, 2017     Published: December 19, 2017


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.

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