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Neoantigen-specific CD8 T cells with high structural avidity preferentially reside in and eliminate tumors. 2023
Julien Schmidt, and
Johanna Chiffelle, and
Marta A S Perez, and
Morgane Magnin, and
Sara Bobisse, and
Marion Arnaud, and
Raphael Genolet, and
Julien Cesbron, and
David Barras, and
Blanca Navarro Rodrigo, and
Fabrizio Benedetti, and
Alexandra Michel, and
Lise Queiroz, and
Petra Baumgaertner, and
Philippe Guillaume, and
Michael Hebeisen, and
Olivier Michielin, and
Tu Nguyen-Ngoc, and
Florian Huber, and
Melita Irving, and
Stéphanie Tissot-Renaud, and
Brian J Stevenson, and
Sylvie Rusakiewicz, and
Denarda Dangaj Laniti, and
Michal Bassani-Sternberg, and
Nathalie Rufer, and
David Gfeller, and
Lana E Kandalaft, and
Daniel E Speiser, and
Vincent Zoete, and
George Coukos, and
Alexandre Harari
Ludwig Institute for Cancer Research, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Agora Cancer Research Center, Lausanne, Switzerland.
The success of cancer immunotherapy depends in part on the strength of antigen recognition by T cells. Here, we characterize the T cell receptor (TCR) functional (antigen sensitivity) and structural (monomeric pMHC-TCR off-rates) avidities of 371 CD8 T cell clones specific for neoantigens, tumor-associated antigens (TAAs) or viral antigens isolated from tumors or blood of patients and healthy donors. T cells from tumors exhibit stronger functional and structural avidity than their blood counterparts. Relative to TAA, neoantigen-specific T cells are of higher structural avidity and, consistently, are preferentially detected in tumors. Effective tumor infiltration in mice models is associated with high structural avidity and CXCR3 expression. Based on TCR biophysicochemical properties, we derive and apply an in silico model predicting TCR structural avidity and validate the enrichment in high avidity T cells in patients' tumors. These observations indicate a direct relationship between neoantigen recognition, T cell functionality and tumor infiltration. These results delineate a rational approach to identify potent T cells for personalized cancer immunotherapy.
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