title: The absence of HLA class I expression in non-small cell lung cancer correlates with the tumor tissue structure and the pattern of T cell infiltration.
abstract: We wanted to analyze whether tumor HLA class I (HLA-I) expression influences the pattern of the immune cell infiltration and stromal cell reaction in the tumor microenvironment. Tumor tissues obtained from 57 patients diagnosed with lung carcinomas were analyzed for HLA expression and leukocyte infiltration. 28 patients out of the 57 were completely negative for HLA-I expression (49.1%) or showed a selective HLA-A locus downregulation (three patients, 5.2%). In 26 out of 57 tumors (47.8%) we detected a positive HLA-I expression but with a percentage of HLA-I negative cells between 10 and 25%. The HLA-I negative phenotype was produced by a combination of HLA haplotype loss and a transcriptional downregulation of β2-microglobulin (β2-m) and LMP2 and LMP7 antigen presentation machinery genes. The analysis and localization of different immune cell populations revealed the presence of two major and reproducible patterns. One pattern, which we designated "immune-permissive tumor microenvironment (TME)," was characterized by positive tumor HLA-I expression, intratumoral infiltration with cytotoxic T-CD8+ cells, M1-inflammatory type macrophages, and a diffuse pattern of FAP+ cancer-associated fibroblasts. In contrast, another pattern defined as "non-immune-permissive TME" was found in HLA-I negative tumors with strong stromal-matrix interaction, T-CD8+ cells surrounding tumor nests, a dense layer of FAP+ fibroblasts and M2/repair-type macrophages. In conclusion, this study revealed marked differences between HLA class I-positive and negative tumors related to tissue structure, the composition of leukocyte infiltration and stromal response in the tumor microenvironment.
authors: Servicio de Análisis Clínicos e Inmunología, UGC Laboratorio Clínico; Hospital Universitario Virgen de las Nieves, Granada, Spain.
authors: Francisco
authors: F
authors: Perea
authors: Servicio de Análisis Clínicos e Inmunología, UGC Laboratorio Clínico; Hospital Universitario Virgen de las Nieves, Granada, Spain.
authors: Mónica
authors: M
authors: Bernal
authors: Servicio de Cirugía Torácica, Hospital Universitario Virgen de las Nieves, Granada, Spain.
authors: Abel
authors: A
authors: Sánchez-Palencia
authors: Servicio de Análisis Clínicos e Inmunología, UGC Laboratorio Clínico; Hospital Universitario Virgen de las Nieves, Granada, Spain.
authors: Javier
authors: J
authors: Carretero
authors: Servicio de Análisis Clínicos e Inmunología, UGC Laboratorio Clínico; Hospital Universitario Virgen de las Nieves, Granada, Spain.
authors: Cristina
authors: C
authors: Torres
authors: Servicio de Cirugía Torácica, Hospital Universitario Virgen de las Nieves, Granada, Spain.
authors: Clara
authors: C
authors: Bayarri
authors: Departamento de Anatomía Patológica, Universidad de Granada, Granada, Spain.
authors: Mercedes
authors: M
authors: Gómez-Morales
authors: Servicio de Análisis Clínicos e Inmunología, UGC Laboratorio Clínico; Hospital Universitario Virgen de las Nieves, Granada, Spain.|Instituto de Investigación Biosanitaria ibs.Granada, Granada, Spain.|Departamento de Bioquímica, Biología Molecular e Inmunología III, Universidad de Granada, Granada, Spain.
authors: Federico
authors: F
authors: Garrido
authors: Servicio de Análisis Clínicos e Inmunología, UGC Laboratorio Clínico; Hospital Universitario Virgen de las Nieves, Granada, Spain.|Instituto de Investigación Biosanitaria ibs.Granada, Granada, Spain.|Departamento de Bioquímica, Biología Molecular e Inmunología III, Universidad de Granada, Granada, Spain.
authors: Francisco
authors: F
authors: Ruiz-Cabello
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D017951:Antigen Presentation; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D002465:Cell Movement; D018450:Disease Progression; D015536:Down-Regulation; D010450:Endopeptidases; D005260:Female; D005347:Fibroblasts / Q000473:pathology; D018093:Gelatinases / Q000032:analysis; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology*; D005805:Genes, MHC Class I; D006680:HLA Antigens / Q000235:genetics / Q000276:immunology*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008264:Macrophages / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000032:analysis; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics; D012697:Serine Endopeptidases / Q000032:analysis; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D019139:Tumor Escape / Q000235:genetics / Q000276:immunology; D059016:Tumor Microenvironment / Q000276:immunology*; D000099167:Fibroblast Activation Protein Alpha
chemical_list: D010450:Endopeptidases; D018093:Gelatinases; D006680:HLA Antigens; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D012697:Serine Endopeptidases; D000099167:Fibroblast Activation Protein Alpha
keywords: HLA class I loss; immune escape; lung cancer; tumor infiltrating lymphocytes