Patient-specific neoantigen peptide-major histocompatibility complex (pMHC) on tumor-associated stromal and vascular cells (Neoantigen-pMHC)

Patient-specific neoantigen peptide-major histocompatibility complex (pMHC) targets on tumor-associated stromal and vascular cells represent a specialized class of immunotherapy targets where mutated, tumor-derived peptides are presented by MHC molecules on non-malignant cells within the tumor microenvironment (TME) (Alspach et al., Nature, 2019). This presentation occurs through the transfer of antigens from tumor cells to surrounding fibroblasts or endothelial cells, a process that renders the tumor's supporting infrastructure vulnerable to T-cell attack (Braumüller et al., Nature, 2013). By engineering T-cells to express receptors (TCRs) specific to these neoantigen-pMHC complexes, clinicians can induce a potent anti-tumor response that includes the collapse of the tumor vasculature and the destruction of the physical stroma (Sprouse et al., Journal of Clinical Investigation, 2023). Targeting the vasculature specifically can lead to rapid tumor debulking by cutting off nutrient supply and facilitating deeper infiltration of immune cells. This approach is particularly valuable for treating solid tumors where the TME often acts as a barrier to traditional therapies. The high specificity of neoantigens, which arise from somatic mutations absent in healthy tissue, significantly reduces the risk of systemic toxicity compared to shared tumor antigens (Blass & Ott, Nature Reviews Clinical Oncology, 2021). However, the requirement for personalized manufacturing and the potential for immune evasion through MHC downregulation remain significant therapeutic challenges.

Other names

Neoepitope-MHC complexTumor-specific antigen-HLA complexTSA-pMHCNeoantigen-HLA complexNeoantigen-pMHC complex

Recognition of the specific peptide-MHC complex by engineered or endogenous T-cell receptors (TCRs), triggering cytotoxic T-lymphocyte (CTL) mediated lysis of the target cell and release of pro-inflammatory cytokines (Schumacher & Schreiber, Science, 2015).