Targeting KRAS Mutations with HLA Class II-restricted TCR for the Immunotherapy in Solid Tumors

KRAS mutation is a significant driving factor of tumor, and KRAS mutation has the highest incidence in solid tumors such as pancreatic cancer and colorectal cancer. Thus, KRAS neoantigen-specific TCR-engineered T cells could be a promising cancer treatment approach for pancreatic cancer. Previous studies had reported that KRAS-reactive TCRs originated from patients' TILs could recognized KRAS neoantigen presented by specific HLA subtypes and remove tumor persistently and . However, TCR drugs are different from antibody drugs in that they are HLA-restricted. The different ethnic distribution of HLA greatly limits the applicability of TCR drugs in Chinese population. In this study, we have identified a KRAS-specific TCR which recognized classII MHC from a colorectal cancer patient. Interestingly, we observed that KRAS-specific TCR-engineered CD4 T cells, not CD8 T cells, demonstrated significant efficacy and in xenograft mouse model, exhibiting stable expression and targeting specificity of TCR when co-cultured with APCs presenting KRAS peptides. TCR-engineered CD4 T cells were co-cultured with APCs loaded with neoantigen, and then HLA subtypes were identified by the secretion of IFN-γ. Collectively, our data suggest that TCR-engineered CD4 T cells can be used to target KRAS mutation presented by HLA-DPB1*03:01 and DPB1*14:01, which provide a high population coverage and are more suitable for the clinical transformation for Chinese, and mediate tumor killing effect like CD8 T cells. This TCR hold promise for precision therapy in immunotherapy of solid tumors as an attractive candidate.