Optimized Anchor-Modified Peptides Targeting Mutated RAS Are Promising Candidates for Immunotherapy

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• RAS mutations are prevalent in ~20% of cancers, acting as key driver mutations associated with poor prognosis.
• The 'undruggable' nature of RAS mutations makes them attractive targets for novel therapeutic strategies like immunotherapy.

Purpose of the Study:

• To identify immunogenic peptides derived from codon 12 mutant RAS (G12A, G12C, G12D, G12R, G12S, G12V).
• To evaluate the potential of these peptides in eliciting robust CD8+ T cell responses for cancer immunotherapy.

Main Methods:

• Identification of mutant RAS peptides binding to HLA-A*02:01 and HLA-A*03:01.
• Modification of peptide anchor residues to enhance HLA binding affinity.
• Generation and characterization of peptide-specific CD8+ T cell responses.
• In vivo vaccination studies in humanized HLA-A2/DR1 mice.

Main Results:

• Identified immunogenic mutant RAS peptides that elicit strong CD8+ T cell responses.
• Anchor residue modifications improved peptide binding to HLA-A*02:01, enhancing T cell recognition.
• Generated cytotoxic T cells specifically lysed RAS-mutated tumor cells.
• Vaccination in mice induced CD8+ T cells reactive against mutant RAS and human cancer cell lines.

Conclusions:

• Mutant RAS-derived peptides can effectively mobilize CD8+ T cell responses.
• Targeting mutant RAS via immunotherapy is a viable and promising strategy for cancer treatment.