Integrating CD4⁺ T cell help for therapeutic cancer vaccination in a preclinical head and neck cancer model

Head and neck squamous cell carcinomas (HNSCC) are well suited for cancer vaccination strategies. In addition to tumor-associated antigens (TAAs) and endogenous retrovirus (ERV) encoded proteins, HNSCCs have a relatively high tumor mutational burden encoding potential neoepitopes. Peptide vaccine candidates are prioritized by predicted high-affinity to major histocompatibility complex (MHC) class I with MHC-II affinity largely not being considered. Herein, we extend previous studies to evaluate therapeutic vaccination in the mouse oral cancer (MOC) 22 model. Two distinct MOC22 derived SLPs were tested–a TSA-oriented mutant intercellular adhesion molecule 1 (mICAM1) and p15E, an ERV encoded antigen. In silico prediction revealed mICAM1 SLP bore strong MHC-I and MHC-II epitopes sharing a mutant residue with vaccination significantly increasing both antigen-specific IFN-γ producing CD4⁺ and CD8⁺ T cells. By contrast, p15E SLP had a predicted high-affinity MHC-I epitope but lacked an MHC-II epitope and vaccination induced antigen-specific CD8⁺ but not CD4⁺ T cell responses. Therapeutic mICAM1 vaccination attenuated tumor growth effectively with mICAM1-specific T cells displaying durable IFN-γ production compared with p15E SLP. Furthermore, mICAM1 SLPs carrying weakened MHC-II binding epitopes were unable to control tumor growth. These data underscore the potential value of therapeutic targeting of HNSCC epitopes and highlight the importance of studying distinct antigen classes in this setting. Moreover, they raise the possibility that, at least in part, CD4⁺ T cell help is critical for cancer vaccination in this preclinical HNSCC model and suggest in silico prediction approaches prioritize overlapping MHC-I and MHC-II epitopes to generate potent cancer vaccines.