Τίτλος:
Spatial analysis and clinical significance of HLA class-I and class-II subunit expression in non–small cell lung cancer
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
Purpose: To analyze the distribution, associated immune contexture, and clinical significance of human leukocyte antigen (HLA) class-I and HLA class-II subunits in non–small cell lung cancer (NSCLC). Experimental Design: Using spatially resolved and quantitative multiplexed immunofluorescence we studied the tumor/stromal tissue distribution, cancer cell–specific defects, and clinicopathologic/survival associations of b2 microglobulin (b2M), HLA-A, and HLA-B,-C heavy chains, as well as HLA class-II b chain in >700 immunotherapy-na€ve NSCLCs from four independent cohorts. Genomic analysis of HLA genes in NSCLC was performed using two publicly available cohorts. Results: Cancer cell–specific downregulation of HLA markers was identified in 30.4% of cases. b2M was downregulated in 9.8% (70/714), HLA-A in 9% (65/722), HLA-B,-C in 12.1% (87/719), and HLA class-II in 17.7% (127/717) of evaluable samples. Concurrent downregulation of b2M, HLA-B,-C, and HLA class-II was commonly identified. Deleterious mutations in HLA genes were detected in <5% of lung malignancies. Tumors with cancer cell–specific b2M downregulation displayed reduced T cells and increased natural killer (NK)–cell infiltration. Samples with cancer cell HLA-A downregulation displayed modest increase in CD8þ T cells and NK-cell infiltration. Samples with cancer cell–selective HLA-B,-C or HLA class-II downregulation displayed reduced T cells and NK-cell infiltration. There was limited association of the markers with clinicopathologic variables and KRAS/EGFR mutations. Cancer cell–selective downregulation of the HLA subunits was associated with shorter overall survival. Conclusions: Our results reveal frequent and differential defects in HLA class-I and HLA class-II protein subunit expression in immunotherapy-na€ve NSCLCs associated with distinct tumor microenvironment composition and patient survival. © American Association for Cancer Research.
Συγγραφείς:
Datar, I.J.
Hauc, S.C.
Desai, S.
Gianino, N.
Henick, B.
Liu, Y.
Syrigos, K.
Rimm, D.L.
Kavathas, P.
Ferrone, S.
Schalper, K.A.
Περιοδικό:
Clinical Cancer Research
Εκδότης:
American Association for Cancer Research Inc.
Λέξεις-κλειδιά:
beta 2 microglobulin; epidermal growth factor receptor; HLA A antigen; HLA antigen; HLA antigen class 1; HLA antigen class 2; HLA B antigen; HLA C antigen; K ras protein, Article; cancer cell; cancer immunotherapy; cancer survival; CD8+ T lymphocyte; cell infiltration; cohort analysis; controlled study; down regulation; gene mutation; genetic analysis; genetic identification; genomics; heavy chain; HLA gene; human; human cell; human tissue; immunofluorescence; major clinical study; multiplex real time polymerase chain reaction; natural killer cell; non small cell lung cancer; overall survival; protein analysis; spatial analysis; tissue distribution; tumor microenvironment
DOI:
10.1158/1078-0432.CCR-20-3655
