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. In contrast, cancer vaccines have great promise for treatment or even prevention, but their efficacy remains an open question. Cancer vaccines often target neoantigens, derived from somatic tumor mutations, encoding a string of multiple neoantigen epitopes with the aim of invigorating endogenous antitumor T cell immunity.
Main Findings
Established in the context of viral infection, immunodominance describes how immune responses focus on a few epitopes in the context of many. In this preprint (not peer reviewed), McCarron et al. investigated immunodominance in response to neoantigen vaccines. Using an mRNA-lipoplex platform, mice were vaccinated with seven murine neoantigens identified from the MC38 colorectal cancer model. All seven neoantigens elicited strong T cell responses individually, but in a shared ‘hepatope’ vaccine, responses to just three neoantigens established dominance over the remaining four. The hierarchy was not intrinsic to the neoantigen itself but due to competition in the context of multi-antigen vaccination. Mechanistically, peptide-MHC-I complex stability correlated with neoantigen dominance, suggesting that longer antigen lifetime may drive dominant T cell responses, at the expense of subdominant ones.
Immunodominance also impacted T cell phenotype, with T cells responding to dominant epitopes predominantly residing in a newly-defined Gzma+Klrg1+ cluster, expressing terminal differentiation and cytotoxicity markers. In contrast, subdominant clones carried a memory precursor effector cell phenotype expressing Gzma+Klf2+. Crucially, these phenotypes were not intrinsic to the target neoantigen but due to the dominance hierarchy. Removal of the dominant neoantigens allowed previously subdominant T cell responses to gain the Gzma+Klrg1+ phenotype. In further experiments, they found that withholding dominant neoantigens until booster doses allowed stronger T cell responses to subdominant neoantigens, with implications for designing vaccine regimens.
Limitations
The clinical relevance of a vaccine-induced immunodominance hierarchy is unclear. The study contained no experiments to determine vaccine efficacy on tumour growth or animal survival. Therefore, we have no insight into the vaccine immunogenicity hierarchy in the context of existing tumors. Would the hierarchy change if a neoantigen response is subdominant by vaccination, but the epitope is highly expressed on the tumor?
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? To win the cancer vaccine game, we can study the competition and ensure every T cell shows up ready to dominate.
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.