Rational discovery of a cancer neoepitope harboring the KRAS G12D driver mutation

Bai, Peng; Zhou, Qiuping; Wei, Pengcheng; Bai, Hua; Chan, Sanny K.; Kappler, John W.; Marrack, Philippa; Yin, Lei

doi:10.1007/s11427-020-1888-1

Cited by 9 publications

(9 citation statements)

References 29 publications

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“…There have been multiple efforts to discover KRAS neoantigens through epitope prediction or structural modeling of peptide-HLA interactions ( Bai et al., 2021 ; Castle et al., 2019 ; Wu et al., 2018 ). However, these primarily leverage affinity-based predictors, which rely on traditional binding assays and a priori knowledge of the peptides to be assayed.…”

Section: Resultsmentioning

confidence: 99%

Systematic discovery and validation of T cell targets directed against oncogenic KRAS mutations

Choi

Goulding

Conn

et al. 2021

Cell Reports Methods

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Section: Resultsmentioning

confidence: 99%

Systematic discovery and validation of T cell targets directed against oncogenic KRAS mutations

Choi

Goulding

Conn

et al. 2021

Cell Reports Methods

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“…The closest TCR residue to HLA-C position 77 or 80 is Glu 49 of the TCRβ chain that interacts with Lys p7 of the peptide but is greater than 7 Å away from HLA-C position 80. Docking TCR10 onto a structure of C*05:01-G12D-10mer using our TCR10-C*08:02-G12D-10mer complex revealed no obvious impact on TCR contacts ( Figure 4—figure supplement 1 ; Bai et al, 2021 ; Sim et al, 2020 ), suggesting the dimorphic positions on C*05 do not directly contact TCR.…”

Section: Resultsmentioning

confidence: 95%

T cells discriminate between groups C1 and C2 HLA-C

Sim

Stotz

et al. 2022

eLife

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Dimorphic amino acids at positions 77 and 80 delineate HLA-C allotypes into two groups, C1 and C2, which associate with disease through interactions with C1 and C2-specific natural killer cell receptors. How the C1/C2 dimorphism affects T cell recognition is unknown. Using HLA-C allotypes that differ only by the C1/C2-defining residues, we found that KRAS-G12D neoantigen-specific T cell receptors (TCR) discriminated between C1 and C2 presenting the same KRAS-G12D peptides. Structural and functional experiments, and immunopeptidomics analysis revealed that Ser77 in C1 and Asn77 in C2 influence amino acid preference near the peptide C-terminus (pW), including the pW-1 position, in which C1 favors small and C2 prefers large residues. This resulted in weaker TCR affinity for KRAS-G12D-bound C2-HLA-C despite conserved TCR contacts. Thus, the C1/C2 dimorphism on its own impacts peptide presentation and HLA-C restricted T cell responses, with implications in disease, including adoptive T cell therapy targeting KRAS-G12D-induced cancers.

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“…Comparing our TCR9a-C*05:01-A18L-9mer structure with that of TCR9a:C*08:02-G12D-9mer revealed no impact on TCR contacts. Further, modelling TCR10 in complex with a recently solved crystal structure of C*05-G12D-10mer revealed no impact on TCR contacts (6JTO) (Bai et al, 2021). The most likely explanation for diminished TCR binding in the presence of C2 -7 -6 -5 -4 -3 -2 -1 0 1 2 0.0 0.5…”

Section: Large Amino Acid Side Chains At Peptide P -1 Position Impair Tcr9a Recognitionmentioning

confidence: 93%

“…Docking TCR10 onto a structure of C*05:01-G12D-10mer using our TCR10-C*08:02-G12D-10mer complex, revealed no obvious impact on TCR contacts (SFig. 4) (Bai et al, 2021;Sim et al, 2020), suggesting the dimorphic positions on C*05 do not directly contact TCR.…”

Section: Impact Of C1/c2 Dimorphism On Tcr Binding To Hla-cmentioning

confidence: 93%

T cells discriminate between groups C1 and C2 HLA-C

Sim

Stotz

et al. 2021

Preprint

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Dimorphic residues at positions 77 and 80 delineate HLA-C allotypes into two groups, C1 and C2, which associate with disease through interactions with C1 and C2-specific natural killer cell receptors. How the C1/C2 dimorphism affects T cell recognition is unknown. Using HLA-C allotypes that differ only by the C1/C2-defining residues, we found that KRAS-G12D neoantigen specific T cell receptors (TCR) discriminated groups C1 and C2 HLA-C, due to effects on peptide presentation and TCR affinity. Structural and functional experiments combined with immunopeptidomics analysis revealed that C1-HLA-C favors smaller amino acids at the peptide C-terminus minus-1 position (pΩ-1), and that larger pΩ-1 residues diminished TCR recognition of C1-HLA-C. After controlling for peptide presentation, TCRs exhibited weaker affinities for C2-HLA-C despite conserved TCR contacts. Thus, the C1/C2 dimorphism impacts peptide presentation and HLA-C restricted T cell responses, with implications in multiple disease contexts including adoptive T cell therapy targeting KRAS-G12D-induced cancers.

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Rational discovery of a cancer neoepitope harboring the KRAS G12D driver mutation

Cited by 9 publications

References 29 publications

Systematic discovery and validation of T cell targets directed against oncogenic KRAS mutations

Systematic discovery and validation of T cell targets directed against oncogenic KRAS mutations

T cells discriminate between groups C1 and C2 HLA-C

T cells discriminate between groups C1 and C2 HLA-C

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