Tumors contain a mixture of T cells with bystander reactivities and reactivities towards different, frequently patient-specific, cancer (neo)antigens. The one-step identification of highly active TCR-antigen pairs in human tumors would be valuable, both as a monitoring tool and to boost T cell reactivities of interest. Here, we develop PAIR-Scan, an HLA-agnostic library-on-library screening technology that identifies functionally active TCR-neoantigen pairs among tens of thousands of candidate pairs in a single step. We demonstrate the value of PAIR-Scan on a range of tumor samples and for the direct identification of TCR-recognized minimal peptides. In addition, we demonstrate that PAIR-Scan correctly ranks TCRs reactive to the same antigen by their relative tumor-killing efficiency. Together, these data demonstrate the value of PAIR-Scan for both the dissection of T cell responses in clinical samples and to generate large-scale datasets for the development of predictive models of TCR reactivity.
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