Purpose:

Developing T-cell or vaccine therapies for pancreatic ductal adenocarcinoma (PDAC) has been challenging because of a lack of knowledge regarding immunodominant, cancer-specific antigens as PDAC are characterized by a scarcity of genomic mutation-associated neoepitopes, and effective approaches to discover them are limited.

Experimental Design:

An advanced mass spectrometry approach was employed to compare the immunopeptidome of PDAC tissues and matched normal tissues from the same patients.

Results:

This study identified HLA class I–binding variant peptides derived from canonical proteins, which had single amino-acid substitutions not attributed to genetic mutations or RNA editing. These amino-acid substitutions appeared to result from translational errors. The variant peptides were predominantly found in tumor tissues, with certain peptides common among multiple patients. Importantly, several of these variant peptides were more immunogenic than their wild-type counterparts.

Conclusions:

The shared noncanonical neoepitopes identified in this study offer promising candidates for vaccine and T-cell therapy development, potentially providing new avenues for immunotherapy in PDAC.

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©2024 The Authors; Published by the American Association for Cancer Research
2024
American Association for Cancer Research
This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license.
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License .
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Supplementary data

Supplementary Dataset S1

Supplementary Dataset S1

- xlsx file
Supplementary Figure S1

Supplementary Figure S1. T2 binding assay of all selected variant peptides.

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Supplementary Figure S2

Supplementary Figure S2. Length histogram of MaxQuant database search identified HLA-Class I bound peptides from paired patient tumor and normal samples.

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Supplementary Figure S3

Supplementary Figure S3. Length histogram of Novor de novo sequencing search identified HLA-Class I bound peptides from paired patient tumor and normal samples.

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Supplementary Figure S4

Supplementary Figure S4. Overlapping peptides extracted from metastatic tumor tissue specimens.

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Supplementary Figure S5

Supplementary Figure S5. Overlapping peptides extracted from primary and metastatic tumor tissue specimens of the same PA_15 patient.

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Supplementary Figure S6

Supplementary Figure S6. Predicted Aligned Error (PAE) plots for the highest five ranked AlphaFold2 model.

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Supplementary Figure S7

Supplementary Figure S7. Predicted per-residue local distance difference test pLDDT for the highest five ranked AlphaFold2 model.

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Supplementary Figure S8

Supplementary Figure S7. Predicted per-residue local distance difference test pLDDT for the highest five ranked AlphaFold2 model.

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Supplementary Table S1

Supplementary Table S1. Variant peptides identified by MS do not correspond to genomic mutations.

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Supplementary Table S2

Supplementary Table S2. Selected variant peptides.

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Supplementary Table S3

Supplementary Table S3. Paired patient tumor and normal specimen information.

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Supplementary Table S4

Supplementary Table S4. MaxQuant database search identified peptide summary.

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Supplementary Table S5

Supplementary Table S5. Novor de novo sequencing identified peptide summary.

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Supplementary Table S6

Supplementary Table S6. List of variant peptides with increased Binding affinity (KD) from normal specimens.

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Supplementary Table S7

Supplementary Table S7. List of variant peptides with increased Binding affinity (KD) from tumor specimens.

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Supplementary Table S8

Supplementary Table S8. List of variant peptides with decreased binding affinity (KD) from normal specimens.

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Supplementary Table S9

Supplementary Table S9. List of variant peptides with decreased Binding affinity (KD) from tumor specimens.

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