Dataset Information

HLA Class I Binding of Mutant EGFR Peptides in NSCLC Is Associated With Improved Survival.

ABSTRACT:

Introduction

Cancer-associated mutations have the potential to generate neoantigens and elicit CD8-positive T-cell-dependent adaptive immune responses. There are currently no reports of CD8-positive T-cells with specificity for neoepitopes generated by EGFR mutations, which are driver oncogenes in a subset of patients with lung cancer.

Methods

We used NETMHCpan 4.0 to identify putative protective human leukocyte antigen (HLA) class I allotypes that are predicted in silico to bind and present mutant EGFR-generated peptides on the basis of predefined criteria. We associated the presence or absence of these alleles with clinical outcomes in patients from The Cancer Genome Atlas with lung adenocarcinoma.

Results

We identified 12 HLA class I alleles that fulfilled the predefined criteria for being protective for EGFR p.L858R and six for EGFR p.E746_A750del, the two most common EGFR mutations in lung cancer. We validated the in silico predictions for peptide-HLA allele binding in vitro. A third (12 of 36) of patients with mostly early stage lung adenocarcinoma in The Cancer Genome Atlas with either EGFR p.L858R or EGFR p.E746_A750del had at least one protective allele in their host genomes. More importantly, patients with protective alleles exhibited better disease-free (hazard ratio: 0.20, 95% confidence interval: 0.05-0.78) and overall survival (hazard ratio: 0.13, 95% confidence interval: 0.02-0.64), and this effect was independent of the EGFR mutation type, stage, age, and sex.

Conclusions

Our data revealed that clinical outcomes were improved in patients with EGFR mutation-positive lung adenocarcinoma who harbored protective HLA class I alleles. Thus, immunity with specificity for mutant EGFR is possible in a subset of patients with early stage lung cancer and portends a better prognosis.

SUBMITTER: Dimou A

PROVIDER: S-EPMC7797166 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Immune checkpoint inhibitors and adoptive lymphocyte transfer-based therapies have shown great therapeutic potential in cancers with high tumor mutational burden (TMB), such as melanoma, but not in cancers with low TMB, such as mutant epidermal growth factor receptor (EGFR)-driven lung adenocarcinoma. Precision immunotherapy is an unmet need for most cancers, particularly for cancers that respond inadequately to immune checkpoint inhibitors. Here, we employed large-scale MS-based proteogenomic profiling to identify potential immunogenic human leukocyte antigen (HLA) class I-presented peptides in melanoma and EGFR-mutant lung adenocarcinoma. Similar numbers of peptides were identified from both tumor types. Cell line and patient-specific databases (DBs) were constructed using variants identified from whole-exome sequencing. A de novo search algorithm was used to interrogate the HLA class I immunopeptidome MS data. We identified 12 variant peptides and several classes of tumor-associated antigen-derived peptides. We constructed a cancer germ line (CG) antigen DB with 285 antigens. This allowed us to identify 40 class I-presented CG antigen-derived peptides. The class I immunopeptidome comprised more than 1000 post-translationally modified (PTM) peptides representing 58 different PTMs, underscoring the critical role PTMs may play in HLA binding. Finally, leveraging de novo search algorithm and an annotated long noncoding RNA (lncRNA) DB, we developed a novel lncRNA-encoded peptide discovery pipeline to identify 44 lncRNA-derived peptides that are presented by class I. We validated tandem MS spectra of select variant, CG antigen, and lncRNA-derived peptides using synthetic peptides and performed HLA class I-binding assays to demonstrate binding to class I proteins. In summary, we provide direct evidence of HLA class I presentation of a large number of variant and tumor-associated peptides in both low and high TMB cancer. These results can potentially be useful for precision immunotherapies, such as vaccine or adoptive cell therapies in melanoma and EGFR-mutant lung cancers.