Uncovering therapeutic TCRs in solid cancer In contrast to CAR-T cell therapy, T cell receptor (TCR)-engineered T cell therapy has shown tremendous efficacy in treating solid cancer patients with advanced disease. To discover TCRs targeting novel tumor antigens with high functional avidity, we leverage our expertise in the analysis of TCR clonotypes and inference of their antigen specificities. Our group has developed a computational framework that allows us to prioritize candidate TCRs from tens of millions of clonotypes identified in cancer patients based on (1) the probable HLA restriction, (2) availability of TCR alpha/beta chain sequences, and (3) association with favorable patient outcome. In the algorithms used for antigen specificity inference, it is assumed that distinct TCR clonotypes with the same MHC-peptide specificity share a short sequence motif within their CDR3. This enables the discovery of TCR clusters with a shared CDR3 motif and thus quantification of the probability that a given HLA allele is the restricting element for the cluster. Once candidate TCRs are identified, we employ HLA display libraries to further uncover their cognate antigens presented on the HLA allele informed by our analysis. The potential clinical utility of promising TCR candidates will be further explored with our in vivo humanized mouse model.