Large-scale profiling of peptides displayed on cancer cell surfaces identified hundreds of potential immunotherapy targets in both high- and low-mutation cancers, including a new class of peptides from noncoding RNA.
44 novel lncRNA-derived peptidesA previously unrecognized class of cancer antigens was discovered from long noncoding RNA, potentially expanding immunotherapy targets beyond traditional mutation-based approaches
What the researchers found
The study profiled the HLA class I immunopeptidome (all peptides displayed on cell surface immune markers) in melanoma (high tumor mutation burden) and EGFR-mutant lung adenocarcinoma (low mutation burden).
Similar numbers of peptides were identified from both cancer types, despite their different mutation rates. Key findings:
- 12 variant peptides from tumor-specific mutations
- 40 cancer germline (CG) antigen-derived peptides from a custom database of 285 CG antigens
- Over 1,000 post-translationally modified (PTM) peptides representing 58 different PTMs
- 44 novel peptides encoded by long noncoding RNA (lncRNA), a previously unrecognized source of cancer antigens
All key findings were validated using synthetic peptide matching and HLA binding assays. The lncRNA-derived peptides represent a completely new class of potential immunotherapy targets.
Why it matters
Immunotherapy works best in high-mutation cancers. Low-mutation cancers like EGFR-driven lung cancer have been harder to target. Finding abundant displayed peptides in both cancer types, plus new sources like lncRNA, expands immunotherapy targets dramatically.
The numbers in context
12 variant peptides; 40 CG antigen peptides; 1000+ PTM peptides (58 types); 44 lncRNA peptides; validated by synthetic matching and HLA binding
How the study worked
Large-scale mass spectrometry-based immunopeptidome profiling of cancer cell lines and patient samples. Databases constructed from whole-exome sequencing. De novo search algorithms used. Custom cancer germline antigen and lncRNA databases created. Key peptides validated with synthetic peptide matching and HLA binding assays.
Who was studied
Melanoma and EGFR-mutant lung adenocarcinoma (human)
What this study cannot tell us
The study profiled cell lines and a limited number of patient samples. Not all identified peptides will be immunogenic (able to trigger an immune response). The lncRNA-derived peptides are novel and need functional validation in immune assays. Some findings may be specific to the HLA types studied.
How to read the evidence
Rigorous proteogenomic study using advanced mass spectrometry with synthetic peptide validation and HLA binding confirmation. However, immunogenicity (ability to trigger immune responses) was not tested, and the number of patient samples was limited.
When this study was published
Published in 2021, this study remains highly relevant as the field of cancer neoantigen discovery and peptide-based immunotherapy continues to rapidly evolve.
The bigger picture
Precision immunotherapy requires knowing which peptides cancer cells display on their surface. This study dramatically expands the catalog of targetable peptides and introduces lncRNA-derived peptides as a completely new class of cancer antigens. For cancers with low mutation burden that don't respond to checkpoint inhibitors, these newly identified peptides could unlock immunotherapy approaches that were previously unavailable.
Questions still open
- How many of the identified peptides can actually trigger anti-tumor immune responses in patients?
- Could lncRNA-derived peptides serve as universal cancer vaccine targets across different tumor types?
- Will these peptide targets improve immunotherapy outcomes in EGFR-mutant lung cancers that currently resist checkpoint inhibitors?
Common questions
What is the immunopeptidome and why does it matter for cancer treatment?
What makes lncRNA-derived peptides special as cancer targets?
Read the original research
Proteogenomic Analysis Unveils the HLA Class I-Presented Immunopeptidome in Melanoma and EGFR-Mutant Lung Adenocarcinoma.
Molecular & cellular proteomics : MCP, 20, 100136
Citation
Qi, Yue A; Maity, Tapan K; Cultraro, Constance M; Misra, Vikram; Zhang, Xu; Ade, Catherine; Gao, Shaojian; Milewski, David; Nguyen, Khoa D; Ebrahimabadi, Mohammad H; Hanada, Ken-Ichi; Khan, Javed; Sahinalp, Cenk; Yang, James C; Guha, Udayan. (2021). Proteogenomic Analysis Unveils the HLA Class I-Presented Immunopeptidome in Melanoma and EGFR-Mutant Lung Adenocarcinoma.. Molecular & cellular proteomics : MCP, 20, 100136. https://doi.org/10.1016/j.mcpro.2021.100136