12 dec. 2025
McCarron et al. (BioRxiv)
Keywords
T cells
mRNA Vaccine
Tumour Neoantigen
Background
Effective vaccines for infectious diseases are one of humanity’s greatest achievements. By contrast, cancer vaccines have great promise for treatment or even prevention, but their clinical efficacy continues to be evaluated. Cancer vaccines often target neoantigens derived from somatic tumour mutations, typically encoding multiple neoantigen epitopes with the aim of invigorating endogenous and de novo T cell-mediated antitumor immunity.
Main Findings
The concept of immunodominance, established in viral infection, describes how immune responses focus on a few epitopes in the context of many. In this preprint (not peer reviewed), McCarron et al. investigate immunodominance in response to neoantigen vaccines.
Using an mRNA–lipid vector platform, mice were vaccinated with seven neoantigens identified from the MC38 colorectal cancer model. All seven neoantigens elicited strong T cell responses individually, but in a shared ‘heptatope’ vaccine responses to three neoantigens established dominance over the remaining four. Mechanistically, peptide–MHC-I complex stability contributed to neoantigen dominance, suggesting that longer antigen lifetime may drive dominant T cell responses at the expense of subdominant ones.
Immunodominance also affected T cell phenotype, with T cells responding to dominant epitopes predominantly having a newly defined GZMA+KLRG1+ phenotype and expressing terminal differentiation and cytotoxicity markers. By contrast, T cell clones responding to subdominant epitopes had GZMA+KLF2+ memory precursor and stem-like features. Crucially, these phenotypes were not intrinsic to the target neoantigen but owing to the dominance hierarchy. Removal of the dominant neoantigens allowed previously subdominant T cell responses to gain the GZMA+KLRG1+ phenotype. Furthermore, withholding dominant neoantigens until boosts allowed stronger subdominant neoantigen T cell responses, which retracted upon boosts containing dominant neoantigens.
Limitations
The impact of the vaccine-induced immunodominance hierarchy on tumour growth or animal survival was not examined in this study. Therefore, how the vaccine hierarchy might differ in the context of existing tumours is unknown. For example, would the hierarchy change if a neoantigen response is subdominant by vaccination but the epitope is highly expressed by the tumour?
Novelty & Significance
Ultimately, this study identifies immunodominance hierarchies as a potential challenge for neoantigen vaccines. These will need to be defined in humans and may differ by vaccine formulation and host genetics, such as HLA type.
Understanding immunodominance hierarchies may also present opportunities to optimize vaccine schedules, particularly for generalized vaccines targeting shared neoantigens. For personalized neoantigen vaccines, a complementary question arises: can omitting immunodominant neoantigens in booster doses create space for more robust subdominant neoantigen responses?
Reviewed by Emery Hoos as part of a cross-institutional journal club between the Icahn School of Medicine at Mount Sinai, the University of Oxford, the Karolinska Institute, the MD Anderson Cancer Center, and the University of Toronto.
The author declares no conflict of interests in relation to their involvement in the review.