Journal Article

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

Kollmeier, Jens, Mairinger, Thomas, Schuler, Martin, Bauer, Torsten, Stephan-Falkenau, Susann, Reis, Henning, Borchert, Sabrina, Mairinger, Fabian D., Schmid, Kurt Werner, Streubel, Anna, Mairinger, Elena, Wiesweg, Marcel, Wessolly, Michael

2022

Overview

Background Immune 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. Methods We 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. Results The 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. Conclusion Pressure 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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Adult / Aged / Aged, 80 and over / Analysis / Antibodies / Antigen processing / Antigenic determinants / Biomarkers / Biomedical and Life Sciences / Biomedicine / Cancer Research / Cancer therapies / Carcinoma, Non-Small-Cell Lung - drug therapy / Carcinoma, Non-Small-Cell Lung - genetics / Carcinoma, Non-Small-Cell Lung - immunology / Care and treatment / Chemotherapy / Computational Biology / Data processing / Deep Learning / Diagnosis / Epitope / Epitopes / FDA approval / Female / Gene expression / Gene set enrichment analysis / Genomes / Health Promotion and Disease Prevention / High-Throughput Nucleotide Sequencing / Humans / Immune checkpoint inhibitors / Immune Checkpoint Inhibitors - pharmacology / Immune Checkpoint Inhibitors - therapeutic use / Immune evasion / Immune system / Immunotherapy / Lung cancer / Lung cancer, Non-small cell / Lung Neoplasms - drug therapy / Lung Neoplasms - genetics / Lung Neoplasms - immunology / Lymphocytes T / Machine learning / Major histocompatibility complex / Male / Massive parallel sequencing / Medicine/Public Health / Methods / Middle Aged / Monoclonal antibodies / Mortality / Mutation / Natural killer cells / Nivolumab - pharmacology / Nivolumab - therapeutic use / Non-small cell lung carcinoma / NSCLC / Oncology / Patient outcomes / Patients / PD-L1 protein / Pressure / Processing escape / Retrospective Studies / Risk factors / Small cell lung carcinoma / Surgical Oncology / Transcriptome - drug effects / Transcriptome - genetics / Transcriptome - immunology / Tumor Escape - drug effects / Tumor Escape - genetics / Tumor Escape - immunology / Tumors