Spatial heterogeneity of the T cell receptor repertoire reflects the mutational landscape in lung cancer

Kroopa Joshi, Marc Robert de Massy, Mazlina Ismail, James L. Reading, Imran Uddin, Annemarie Woolston, Emine Hatipoglu, Theres Oakes, Rachel Rosenthal, Thomas Peacock, Tahel Ronel, Mahdad Noursadeghi, Virginia Turati, Andrew Georgiou, Andrew J. S. Furness, Yien Ning Sophia Wong, Assma Ben Aissa, Mariana Werner Sunderland, Mariam Jamal-Hanjani, Selvaraju VeeriahNicolai Juul Birkbak, Gareth A. Wilson, Crispin T Hiley, Ehsan Ghorani, José Afonso Guerra-Assunção, Javier Herrero, Tariq Enver, Sine R. Hadrup, Allan Hackshaw, Karl S Peggs, Nicholas McGranahan, Charles Swanton, TRACERx Consortium, Sergio A. Quezada, Benny Chain

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Somatic mutations together with immunoediting drive extensive heterogeneity within non-small-cell lung cancer (NSCLC). Herein we examine heterogeneity of the T cell antigen receptor (TCR) repertoire. The number of TCR sequences selectively expanded in tumors varies within and between tumors and correlates with the number of nonsynonymous mutations. Expanded TCRs can be subdivided into TCRs found in all tumor regions (ubiquitous) and those present in a subset of regions (regional). The number of ubiquitous and regional TCRs correlates with the number of ubiquitous and regional nonsynonymous mutations, respectively. Expanded TCRs form part of clusters of TCRs of similar sequence, suggestive of a spatially constrained antigen-driven process. CD8+ tumor-infiltrating lymphocytes harboring ubiquitous TCRs display a dysfunctional tissue-resident phenotype. Ubiquitous TCRs are preferentially detected in the blood at the time of tumor resection as compared to routine follow-up. These findings highlight a noninvasive method to identify and track relevant tumor-reactive TCRs for use in adoptive T cell immunotherapy.
Original languageEnglish
JournalNature Medicine
Issue number10
Pages (from-to)1549-1559
Publication statusPublished - 2019


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