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Published on: July 25, 2020
Characterization of shared neoantigens landscape in Mismatch Repair Deficient Endometrial Cancer
Elisa De Paolis1,2, Camilla Nero3,4, Elisa Micarelli5
1Departmental Unit of Molecular and Genomic Diagnostics, Genomics Research Core Facility, Gemelli Science and Technology Park (GSTeP), Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.
Abstract:
Endometrial cancer (EC) with Mismatch Repair deficiency (MMRd) is characterized by the accumulation of insertions/deletions at microsatellite sites. These mutations lead to the synthesis of frameshift peptides (FSPs) that represent tumor-specific neoantigens (nAg) proved to be shared across patients/tumors with MMRd. In this study, we explored the feasibility of a nAg-based cancer vaccination design in EC with MMRd. We adopted a whole exome sequencing approach and ad hoc bioinformatics pipelines to characterize FSPs in 35 patients with EC. A mean of 146 mutated mononucleotide repeats (MNRs) was identified with enrichment in the patients' group with MLH1 impairment. A high coverage emerged from the comparative analysis of the EC FSPs with the content of the previously validated NOUS-209 vaccine. We obtained pieces of evidence of FSPs translation as expressed proteins from Ribo-seq, supporting the potential as the target of vaccination. The development of a nAgs-based vaccine strategy in MMRd EC may be further explored.
Insights
This study explored using tumor neoantigens (nAg) from endometrial cancer (EC) with Mismatch Repair deficiency (MMRd) for cancer vaccines. Researchers found shared frameshift peptides (FSPs) in MMRd EC patients, suggesting potential vaccine targets.
Area of Science:
- Oncology
- Immunology
- Genomics
Background:
- Endometrial cancer (EC) with Mismatch Repair deficiency (MMRd) exhibits microsatellite instability, leading to frameshift peptides (FSPs).
- These FSPs can function as tumor-specific neoantigens (nAg) shared across MMRd tumors.
- Targeting these shared nAgs presents a potential strategy for cancer vaccination.
Purpose of the Study:
- To investigate the feasibility of a neoantigen-based cancer vaccination strategy in MMRd EC.
- To characterize FSPs in EC patients with MMRd.
- To assess the potential of identified FSPs as vaccine targets.
Main Methods:
- Whole exome sequencing was performed on 35 EC patients.
- Bioinformatics pipelines were used to identify and characterize FSPs.
- Comparative analysis was conducted between identified FSPs and the NOUS-209 vaccine.
- Ribosome sequencing (Ribo-seq) was employed to detect FSP expression.
Main Results:
- A mean of 146 mutated mononucleotide repeats (MNRs) were identified in the study cohort.
- MNR enrichment was observed in patients with MLH1 impairment.
- A significant overlap was found between EC FSPs and the NOUS-209 vaccine's neoantigen content.
- Evidence of FSP translation into expressed proteins was obtained via Ribo-seq.
Conclusions:
- Frameshift peptides in MMRd EC are translatable and represent shared neoantigens.
- These findings support the exploration of neoantigen-based vaccine strategies for MMRd EC.
- The identified FSPs hold promise as targets for novel cancer immunotherapies.
