Neoantigen-specific CD8 T cells with high structural avidity preferentially reside in and eliminate tumors

Julien Schmidt; Johanna Chiffelle; Marta A S Perez; Morgane Magnin; Sara Bobisse; Marion Arnaud; Raphael Genolet; Julien Cesbron; David Barras; Blanca Navarro Rodrigo; Fabrizio Benedetti; Alexandra Michel; Lise Queiroz; Petra Baumgaertner; Philippe Guillaume; Michael Hebeisen; Olivier Michielin; Tu Nguyen-Ngoc; Florian Huber; Melita Irving; Stéphanie Tissot-Renaud; Brian J Stevenson; Sylvie Rusakiewicz; Denarda Dangaj Laniti; Michal Bassani-Sternberg; Nathalie Rufer; David Gfeller; Lana E Kandalaft; Daniel E Speiser; Vincent Zoete; George Coukos; Alexandre Harari

doi:10.1038/s41467-023-38946-z

Neoantigen-specific CD8 T cells with high structural avidity preferentially reside in and eliminate tumors

Nat Commun. 2023 Jun 6;14(1):3188. doi: 10.1038/s41467-023-38946-z.

Authors

Julien Schmidt^#^{1

2

3}, Johanna Chiffelle^#^{1

2}, Marta A S Perez^#^{1

4}, Morgane Magnin^#^{1

2}, Sara Bobisse^{1

2}, Marion Arnaud^{1

2}, Raphael Genolet^{1

2}, Julien Cesbron^{1

2}, David Barras^{1

2}, Blanca Navarro Rodrigo^{1

2}, Fabrizio Benedetti^{1

2}, Alexandra Michel^{1

2}, Lise Queiroz^{1

2}, Petra Baumgaertner^{1

3}, Philippe Guillaume^{1

2

3}, Michael Hebeisen¹, Olivier Michielin⁵, Tu Nguyen-Ngoc¹, Florian Huber^{1

2}, Melita Irving¹, Stéphanie Tissot-Renaud^{1

3}, Brian J Stevenson^{1

2

4}, Sylvie Rusakiewicz^{1

3}, Denarda Dangaj Laniti^{1

2}, Michal Bassani-Sternberg^{1

2}, Nathalie Rufer¹, David Gfeller^{1

4}, Lana E Kandalaft^{1

2

3}, Daniel E Speiser¹, Vincent Zoete^{1

4}, George Coukos^{1

2

5}, Alexandre Harari^{6

7}

Affiliations

¹ Ludwig Institute for Cancer Research, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Agora Cancer Research Center, Lausanne, Switzerland.
² Center for Cell Therapy, Department of Oncology, Lausanne University Hospital, Lausanne, Switzerland.
³ Center of Experimental Therapeutics, Department of Oncology, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
⁴ Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland.
⁵ Department of Oncology, Lausanne University Hospital, Lausanne, Switzerland.
⁶ Ludwig Institute for Cancer Research, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Agora Cancer Research Center, Lausanne, Switzerland. Alexandre.Harari@chuv.ch.
⁷ Center for Cell Therapy, Department of Oncology, Lausanne University Hospital, Lausanne, Switzerland. Alexandre.Harari@chuv.ch.

^# Contributed equally.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antigens, Neoplasm
CD8-Positive T-Lymphocytes
Clone Cells / metabolism
Melanoma* / metabolism
Mice
Receptors, Antigen, T-Cell / metabolism

Substances

Receptors, Antigen, T-Cell
Antigens, Neoplasm