This project addresses a critical challenge in cancer treatment: improving adoptive cell therapy (ACT) for solid tumors, where limited neoantigen presentation restricts therapeutic efficacy. Current ACT approaches face barriers including poor antigen availability, tumor microenvironment suppression, and the difficulty in targeting shared, treatment-resistant neoantigens across tumor types. In this project we innovate by discovering neoantigens such as KRAS G12V and leveraging chemotherapy to enhance antigen presentation, thereby improving ACT efficacy in tumors with scarce neoantigens. The primary objective is to identify novel, recurrent neoantigens—such as KRAS G12V—and develop T cell receptors (TCRs) capable of specifically recognizing these targets, thereby enhancing the precision and potency of ACT.
To overcome resistance and heterogeneity in metastatic cancers, we developed SpotNeoMet, a data-driven pipeline that systematically detects recurrent neoantigens associated with treatment resistance. This innovative approach supports the discovery of shared immunogenic peptides and cognate TCRs, expanding immunotherapy options for patients with resistant tumors.
Furthermore, by integrating genomics, immunopeptidomics, and structural modeling, we explored aberrant peptides arising from dysregulated protein translation, revealing new immune targets and introducing a new immunotherapy axis. We uncovered key immune escape mechanisms, such as macrophage migration inhibitory factor (MIF), providing potential therapeutic targets in immune-resistant cancers.
The expected impact of this research is significant—advancing the understanding of tumor-immune interactions and offering translational strategies to improve ACT efficacy in challenging solid tumor contexts. These advances hold promise to overcome current barriers in immunotherapy, expanding treatment accessibility and improving outcomes for patients with resistant or heterogeneous tumors.
