Digital gene expression analysis of NSCLC-patients reveals strong immune pressure, resulting in an immune escape under immunotherapy

BMC Cancer

Marcel Wiesweg¹  Thomas Mairinger²  Anna Streubel²  Susann Stephan-Falkenau²  Martin Schuler³  Kurt Werner Schmid⁴  Elena Mairinger⁴  Henning Reis⁵  Fabian D. Mairinger⁶  Sabrina Borchert⁶  Michael Wessolly⁶  Jens Kollmeier⁷  Torsten Bauer⁷ 

[1] Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Hufelandstrasse 55, 45147, Essen, Germany;Department of Tissue Diagnostics, Helios Klinikum Emil von Behring, Berlin, Germany;German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Hufelandstrasse 55, 45147, Essen, Germany;Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Hufelandstrasse 55, 45147, Essen, Germany;Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45147, Essen, Germany;Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45147, Essen, Germany;Dr. Senckenberg Institute of Pathology, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt, Germany;Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45147, Essen, Germany;German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Hufelandstrasse 55, 45147, Essen, Germany;Lungenklinik Heckeshorn, Helios Klinikum Emil von Behring, Berlin, Germany;

关键词: Massive parallel sequencing;    NSCLC;    Immunotherapy;    Epitope;    Processing escape;    Deep learning;   

DOI  :  10.1186/s12885-021-09111-w

来源: Springer

【 摘 要 】

BackgroundImmune checkpoint inhibitors (ICIs) are currently one of the most promising therapy options in the field of oncology. Although the first pivotal ICI trial results were published in 2011, few biomarkers exist to predict their therapy outcome. PD-L1 expression and tumor mutational burden (TMB) were proven to be sometimes-unreliable biomarkers. We have previously suggested the analysis of processing escapes, a qualitative measurement of epitope structure alterations under immune system pressure, to provide predictive information on ICI response. Here, we sought to further validate this approach and characterize interactions with different forms of immune pressure.MethodsWe identified a cohort consisting of 48 patients with advanced non-small cell lung cancer (NSCLC) treated with nivolumab as ICI monotherapy. Tumor samples were subjected to targeted amplicon-based sequencing using a panel of 22 cancer-associated genes covering 98 mutational hotspots. Altered antigen processing was predicted by NetChop, and MHC binding verified by NetMHC. The NanoString nCounter® platform was utilized to provide gene expression data of 770 immune-related genes. Patient data from 408 patients with NSCLC were retrieved from The Cancer Genome Atlas (TCGA) as a validation cohort.ResultsThe two immune escape mechanisms of PD-L1 expression (TPS score) (n = 18) and presence of altered antigen processing (n = 10) are mutually non-exclusive and can occur in the same patient (n = 6). Both mechanisms have exclusive influence on different genes and pathways, according to differential gene expression analysis and gene set enrichment analysis, respectively. Interestingly, gene expression patterns associated with altered processing were enriched in T cell and NK cell immune activity. Though both mechanisms influence different genes, they are similarly linked to increased immune activity.ConclusionPressure from the immune system will lay the foundations for escape mechanisms, leading to acquisition of resistance under therapy. Both PD-L1 expression and altered antigen processing are induced similarly by pronounced immunoactivity but in different context. The present data help to deepen our understanding of the underlying mechanisms behind those immune escapes.

【 授权许可】

CC BY