Abstract
BackgroundNeoantigens are presented on the cancer cell surface by peptide-restricted human leukocyte antigen (HLA) proteins and can subsequently activate cognate T cells. It has been hypothesized that the observed somatic mutations in tumors are shaped by immunosurveillance.MethodsWe investigated all somatic mutations identified in The Cancer Genome Atlas (TCGA) Skin Cutaneous Melanoma (SKCM) samples. By applying a computational algorithm, we calculated the binding affinity of the resulting neo-peptides and their corresponding wild-type peptides with the major histocompatibility complex (MHC) Class I complex. We then examined the relationship between binding affinity alterations and mutation frequency.ResultsOur results show that neoantigens derived from recurrent mutations tend to have lower binding affinities with the MHC Class I complex compared to peptides from non-recurrent mutations. Tumor samples harboring recurrent SKCM mutations exhibited lower immune infiltration levels, indicating a relatively colder immune microenvironment.ConclusionsThese results suggested that the occurrences of somatic mutations in melanoma have been shaped by immunosurveillance. Mutations that lead to neoantigens with high MHC class I binding affinity are more likely to be eliminated and thus are less likely to be present in tumors.
Highlights
Cancer is a genetic disease caused by genomic abnormalities including somatic mutations, which result in mutated antigens
We investigated the non-synonymous somatic mutations identified in the The Cancer Genome Atlas (TCGA) Skin Cutaneous Melanoma (SKCM) samples
54 binding scores were calculated for the nine peptides that resulted from a mutation with the six human leukocyte antigen (HLA) class I alleles
Summary
Cancer is a genetic disease caused by genomic abnormalities including somatic mutations, which result in mutated antigens (i.e., neoantigens). Neoantigens derived from non-synonymous mutations can be recognized, bound, and presented on the tumor cell surface by major histocompatibility complex (MHC) proteins. According to the theory of immunosurveillance, a functional immune system can recognize and eliminate tumor cells harboring antigenic mutations [1, 7]. Tumor cells presenting immune-activating neoantigens are more likely to be eliminated through T-cell recognition as compared to non-immunogenic mutations [8– 10]. Somatic mutations abrogating essential immune functions (e.g., mutations in B2M and HLA genes) are generally positively selected for in tumors and are common in different types of cancers [11]. The majority of somatic mutations are under negative selection during the tumorigenesis by immunosurveillance. Other studies have suggested that neoantigen selection by the immune system becomes negligible in untreated tumor samples when considering mutational signatures [18, 19]. We examined the relationship between binding affinity alterations and mutation frequency
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