Mutant KRAS peptide-Major Histocompatibility Complex class II complex (mKRAS-MHC II) (mKRAS-MHC II)

The mutant KRAS peptide-MHC class II complex is a neoantigen target formed when mutated KRAS proteins, such as G12D or G12V, are processed and presented on the cell surface via Major Histocompatibility Complex (MHC) class II molecules (Tran et al., 2016, NEJM). This complex is a critical target for immunotherapy because KRAS mutations are prevalent in highly aggressive cancers, including over 90% of pancreatic ductal adenocarcinomas and approximately 40% of colorectal cancers (Prior et al., 2020, Cancer Research). Unlike MHC class I targets which are recognized by CD8+ T cells, MHC class II targets are primarily recognized by CD4+ T cells, though engineered T-cell receptors (TCRs) can be used in various T-cell subsets to trigger a potent anti-tumor response (Lo et al., 2021, Science Immunology). Therapeutic strategies targeting this complex include TCR-engineered T-cell (TCR-T) therapy and neoantigen vaccines, which aim to exploit the high specificity of the TCR for the mutant epitope over the wild-type sequence (Bear et al., 2022, NEJM). Clinical trials have shown that adoptive transfer of T cells specific for the KRAS G12D mutation presented by HLA-DRB1*08:01 can lead to objective clinical responses in patients with metastatic colorectal cancer (Tran et al., 2016, NEJM). However, the success of these therapies is constrained by the requirement for specific HLA alleles and the potential for tumor escape through HLA downregulation or loss of heterozygosity (Reis et al., 2022, Nature Communications).

Other names

KRAS neoantigen-MHC II complexMutant KRAS epitopeKRAS G12D-HLA-DRB1*08:01 complexKRAS G12V-HLA-DQB1*03:02 complexKRAS G12R-HLA-DRB1*08:01 complex

Binding of specific T-cell receptors (TCRs) to the mutant KRAS peptide presented on MHC class II molecules, leading to T-cell activation, cytokine release, and targeted lysis of tumor cells (Tran et al., 2016, NEJM).