<p>A Novel Epitope Quality-Based Immune Escape Mechanism Reveals Patient’s Suitability for Immune Checkpoint Inhibition</p>

Abstract

Background: Immune checkpoint inhibition, especially the blockade of PD-1 and PD-L1, has become one of the most thriving therapeutic approaches in modern oncology. Immune evasion caused by altered tumor epitope processing (so-called processing escapes) may be one way to explain immune checkpoint inhibition therapy failure. In the present study, we aim to demonstrate the effects of processing escapes on immunotherapy outcome in NSCLC patients. Patients and Methods: Whole exome sequencing data of 400 NSCLC patients (AdC and SCC) were extracted from the TCGA database. The ICB cohort was composed of primary tumor probes from 48 NSCLC patients treated with nivolumab. Mutations were identified by targeted amplicon-based sequencing including hotspots and whole exomes of 22 genes. The effect of mutations on proteasomal processing was evaluated by deep learning methods previously trained on 1260 known MHC-I ligands. Cox regression modelling was used to determine the influence on overall survival. Results: In the TCGA cohort, processing escapes were associated with decreased overall survival (p= 0.0140). In the ICB cohort, patients showing processing escapes in combination with high levels of PD-L1 (n=8/48) also showed significantly decreased overall survival, independently of mutational load or PD-L1 status. Conclusion: The concept of altered epitope processing may help to understand immunotherapy failure. Especially when combined with PD-L1 status, this method can be used as a biomarker to identify patients not suitable for immunotherapy.

Proteasomal Processing Immune Escape Mechanisms in Platinum-Treated Advanced Bladder Cancer

“…One way of achieving this is altering the presented protein fragment’s size and therefore affinity to bind to the MHC-class I-complex or recognizability to the TCR, which has been identified as a pivotal mechanism in viral infections [ 40 , 41 ]. We have recently shown this mechanism to be active through exonic mutations leading to the altered proteasomal processing of epitopes (“processing escapes”) in lung cancer [ 19 ]. As a result of changes in the chemical composition of the amino acid sequence due to non-synonymous somatic mutations, the proteasomal cleavage properties may change as the different proteasomal subunits show different cleavage preferences for acidic, basic, or hydrophobic amino acids [ 42 ].…”

“…We have previously shown that alterations in proteasomal antigen processing can be a general mechanism of immune escape in lung cancer [ 19 ]. In the present study, we analyzed if this mechanism is also effective in advanced platinum-treated BC.…”

Engineering neoantigen vaccines to improve cancer personalized immunotherapy

“…These may bring on ineffective neoantigen-specific T cell activation owing to a loss of binding affinity between the neoantigen and the MHC I complex or alteration of the complex's affinity for binding to the TCR. Lung cancer 105 and advanced bladder cancer 106 had a latent immune escape mechanism by altering proteasome antigen processsing. Meanwhile, HLA loss or mutation affected the stability of MHC and production of HLA enhancers, thus, disrupting antigen presentation, which provided an alternative mechanism for immune evasion 103 , 107 , 108 .…”

Digital Gene Expression Analysis of Epithelioid and Sarcomatoid Mesothelioma Reveals Differences in Immunogenicity

“…Modern immunotherapeutic approaches have already been investigated in clinical trials in MPM [56][57][58]. One possible explanation for different responses might be in the processing and presentation of tumor-specific epitopes [59,60] important for the activation of tumor-specific T-cells [61]. A complex intracellular pathway is involved in processing these antigenic peptides (Figure S2).…”