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

Abstract

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.

Therapeutic Vaccination in Head and Neck Squamous Cell Carcinoma—A Review

“…Antigen-presenting cells (APC), such as dendritic cells (DC), take up these tumor antigens from circulation and present them to host T cells, leading to their activation and differentiation into effector T cells and memory T cells. Subsequently, the reactivated T cells (CTL) carry out tumor antigen -specific cytolytic activity ( ASIR ) by releasing cytokines such as interferon (IFN)-γ/tumor necrosis factor (TNF)-α, perforin, and granzyme, which eradicate cancer cells [ 18 , 19 ]. The T cell responses also include secreting IL-2, which supports cellular immunity, and increasing the expression of CD80/86 costimulatory signals, which are essential for T cell priming [ 19 ].…”

“…Subsequently, the reactivated T cells (CTL) carry out tumor antigen -specific cytolytic activity ( ASIR ) by releasing cytokines such as interferon (IFN)-γ/tumor necrosis factor (TNF)-α, perforin, and granzyme, which eradicate cancer cells [ 18 , 19 ]. The T cell responses also include secreting IL-2, which supports cellular immunity, and increasing the expression of CD80/86 costimulatory signals, which are essential for T cell priming [ 19 ].…”

“…Currently, most of the peptide-based vaccines being evaluated in clinical trials target one of the CTAs, differentiation antigens, or oncofetal antigens. In addition, in most of these peptide vaccines, adjuvants such as toll-like receptor (TLR) are used to potentiate the otherwise modest immunogenicity of these TAAs [ 19 ]. The other noteworthy strategy to deliver a tumor antigen or epitope is to utilize viral vectors carrying expression cassettes.…”

“…The first and most extensively evaluated viral-based therapeutic vaccine trials involved the poxviridae family, such as vaccinia, modified vaccinia strain Ankara (MVA), and the avipoxviruses (fowlpox and canarypox). Subsequently, recombinant adenovirus gained popularity owing to the ease of engineering and propagation for clinical use, as well as due to their ability to transduce both dividing and non-dividing cells for the high expression of transgenes [ 19 ].…”

Antitumor Peptide-Based Vaccine in the Limelight

“…Although CTLs are potent in killing tumors, HTLs can directly exert antitumor effects through the production of cytokines such as IFN-γ, TNF-α, granzyme-B, and perforin [29][30][31]. Moreover, several reports have shown that HTLs are more important than CTLs in cancer immunotherapy by the direct tumor killing and education of CTLs or natural killer (NK) cells [32][33][34][35]. Because the support of HTLs to prime CTLs is only applied to high-avidity CTLs [36], high-avidity CTLs can be selectively activated with HTL epitopecombined CTL vaccines, whereas low-avidity CTLs compromise high-avidity CTLs with CTL vaccines alone.…”