Characterization of CD8+ T-cell responses to non-anchor-type HLA class I neoantigens with single amino-acid substitutions
CD8+ T cells are capable of recognizing mutation-derived neoantigens displayed by HLA class I molecules, thereby exhibiting the ability to distinguish between cancer and normal cells. However, accumulating evidence has shown that only a small fraction of nonsynonymous somatic mutations give rise to...
Main Authors: | , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Taylor & Francis Group
2021-01-01
|
Series: | OncoImmunology |
Subjects: | |
Online Access: | http://dx.doi.org/10.1080/2162402X.2020.1870062 |
id |
doaj-cd207c8fc7084b698ed44490a7e0fda9 |
---|---|
record_format |
Article |
spelling |
doaj-cd207c8fc7084b698ed44490a7e0fda92021-01-26T11:50:11ZengTaylor & Francis GroupOncoImmunology2162-402X2021-01-0110110.1080/2162402X.2020.18700621870062Characterization of CD8+ T-cell responses to non-anchor-type HLA class I neoantigens with single amino-acid substitutionsTomoyo Shinkawa0Serina Tokita1Munehide Nakatsugawa2Yasuhiro Kikuchi3Takayuki Kanaseki4Toshihiko Torigoe5Sapporo Medical UniversitySapporo Dohto HospitalTokyo Medical University Hachioji Medical CenterSapporo Medical UniversitySapporo Medical UniversitySapporo Medical UniversityCD8+ T cells are capable of recognizing mutation-derived neoantigens displayed by HLA class I molecules, thereby exhibiting the ability to distinguish between cancer and normal cells. However, accumulating evidence has shown that only a small fraction of nonsynonymous somatic mutations give rise to clinically relevant neoantigens. The properties of such neoantigens, which must be presented by HLA and immunogenic to induce a T-cell response, remain elusive. In this study, we explored the HLA class I ligandome of a human cancer cell line with microsatellite instability using a proteogenomic approach. The results demonstrated that neoantigens accounted for only 0.34% of the HLA class I ligandome, and most neoantigens were encoded by genes with abundant expression. Thereafter, T-cell responses were prioritized, and immunodominant neoantigens were defined using naive CD8+ T cells derived from healthy donors. AKF9, an immunogenic neoantigen with a mutation at a non-anchor position, formed a stable peptide-HLA complex. T-cell responses were analyzed against a panel of AKF9 variants with single amino-acid substitutions, in which mutations did not alter the high HLA-binding affinity and stability. The responses varied across individuals, demonstrating the impact of heterogeneous T-cell repertoires in this human cancer model. Moreover, responses were biased toward a variant group with large structural changes compared to the wild-type peptide. Thus, naive T-cell induction can be attributed to multiple determinants. Combining structural dissimilarity with gene-expression levels, HLA-binding affinity, and stability may further help prioritize the immunogenicity of non-anchor-type neoantigens.http://dx.doi.org/10.1080/2162402X.2020.1870062tumor antigenneoantigencd8+ t cellsimmunogenicityhla ligandome |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Tomoyo Shinkawa Serina Tokita Munehide Nakatsugawa Yasuhiro Kikuchi Takayuki Kanaseki Toshihiko Torigoe |
spellingShingle |
Tomoyo Shinkawa Serina Tokita Munehide Nakatsugawa Yasuhiro Kikuchi Takayuki Kanaseki Toshihiko Torigoe Characterization of CD8+ T-cell responses to non-anchor-type HLA class I neoantigens with single amino-acid substitutions OncoImmunology tumor antigen neoantigen cd8+ t cells immunogenicity hla ligandome |
author_facet |
Tomoyo Shinkawa Serina Tokita Munehide Nakatsugawa Yasuhiro Kikuchi Takayuki Kanaseki Toshihiko Torigoe |
author_sort |
Tomoyo Shinkawa |
title |
Characterization of CD8+ T-cell responses to non-anchor-type HLA class I neoantigens with single amino-acid substitutions |
title_short |
Characterization of CD8+ T-cell responses to non-anchor-type HLA class I neoantigens with single amino-acid substitutions |
title_full |
Characterization of CD8+ T-cell responses to non-anchor-type HLA class I neoantigens with single amino-acid substitutions |
title_fullStr |
Characterization of CD8+ T-cell responses to non-anchor-type HLA class I neoantigens with single amino-acid substitutions |
title_full_unstemmed |
Characterization of CD8+ T-cell responses to non-anchor-type HLA class I neoantigens with single amino-acid substitutions |
title_sort |
characterization of cd8+ t-cell responses to non-anchor-type hla class i neoantigens with single amino-acid substitutions |
publisher |
Taylor & Francis Group |
series |
OncoImmunology |
issn |
2162-402X |
publishDate |
2021-01-01 |
description |
CD8+ T cells are capable of recognizing mutation-derived neoantigens displayed by HLA class I molecules, thereby exhibiting the ability to distinguish between cancer and normal cells. However, accumulating evidence has shown that only a small fraction of nonsynonymous somatic mutations give rise to clinically relevant neoantigens. The properties of such neoantigens, which must be presented by HLA and immunogenic to induce a T-cell response, remain elusive. In this study, we explored the HLA class I ligandome of a human cancer cell line with microsatellite instability using a proteogenomic approach. The results demonstrated that neoantigens accounted for only 0.34% of the HLA class I ligandome, and most neoantigens were encoded by genes with abundant expression. Thereafter, T-cell responses were prioritized, and immunodominant neoantigens were defined using naive CD8+ T cells derived from healthy donors. AKF9, an immunogenic neoantigen with a mutation at a non-anchor position, formed a stable peptide-HLA complex. T-cell responses were analyzed against a panel of AKF9 variants with single amino-acid substitutions, in which mutations did not alter the high HLA-binding affinity and stability. The responses varied across individuals, demonstrating the impact of heterogeneous T-cell repertoires in this human cancer model. Moreover, responses were biased toward a variant group with large structural changes compared to the wild-type peptide. Thus, naive T-cell induction can be attributed to multiple determinants. Combining structural dissimilarity with gene-expression levels, HLA-binding affinity, and stability may further help prioritize the immunogenicity of non-anchor-type neoantigens. |
topic |
tumor antigen neoantigen cd8+ t cells immunogenicity hla ligandome |
url |
http://dx.doi.org/10.1080/2162402X.2020.1870062 |
work_keys_str_mv |
AT tomoyoshinkawa characterizationofcd8tcellresponsestononanchortypehlaclassineoantigenswithsingleaminoacidsubstitutions AT serinatokita characterizationofcd8tcellresponsestononanchortypehlaclassineoantigenswithsingleaminoacidsubstitutions AT munehidenakatsugawa characterizationofcd8tcellresponsestononanchortypehlaclassineoantigenswithsingleaminoacidsubstitutions AT yasuhirokikuchi characterizationofcd8tcellresponsestononanchortypehlaclassineoantigenswithsingleaminoacidsubstitutions AT takayukikanaseki characterizationofcd8tcellresponsestononanchortypehlaclassineoantigenswithsingleaminoacidsubstitutions AT toshihikotorigoe characterizationofcd8tcellresponsestononanchortypehlaclassineoantigenswithsingleaminoacidsubstitutions |
_version_ |
1724322818957508608 |