Abstract
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.
Highlights
In 2018, 9.6 million people died from cancer or its associated ailments
Signs of altered epitope processing were frequently identified in the discovery cohort Based on the NetChop analysis, around 40% of all identified non-synonymous mutations were associated with changes in proteasomal processing, which lead to structural changes of presented epitopes
NetMHC analysis revealed that only 11% were still capable to either bind Major histocompatibility complex (MHC) class I molecules in a sufficient manner or trigger an impactful anti-cancer immune response
Summary
In 2018, 9.6 million people died from cancer or its associated ailments. Non-small cell lung cancer (NSCLC) is the most common lung cancer accounting for about 80% of cases. Tobacco exposure is considered the most prominent risk factor for developing lung cancer. It is estimated that 80% of all NSCLC cases are associated with tobacco smoking in various countries including the United States [5]. Immune checkpoint inhibitors (ICIs) are currently one of the most promising therapy options in the field of oncology. The first pivotal ICI trial results were published in 2011, few biomarkers exist to predict their therapy outcome. 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. We sought to further validate this approach and characterize interactions with different forms of immune pressure
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