bioRxiv : the preprint server for biology · 2026
PAIR-Scan: Single-step identification of highly potent TCR-neoantigen pairs through library-on-library screening.
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Messemaker Marius, Richterich Connor A, Wenner Jule, Ma Yiting, Moravec Živa, Voogd Rhianne, Mussmann Maike, de Paauw Sam, Kwee Bjørn P Y, Geerligs Jeroen, Morris Ben, Winkler Yaël, Springer Babet O, van den Brekel Floris T B T, Urbanus Jos, Guislain Aurélie, Alfaiate Nuno, van Diepen Frank, van Baalen Martijn, Nicolet Benoit P, Haanen John B A G, Wu Catherine J, Huuhtanen Jani, Scheper Wouter, Schumacher Ton N
Аннотация
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.