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

Item Type:Article
Title:Spatial heterogeneity of the T cell receptor repertoire reflects the mutational landscape in lung cancer
Creators Name:Joshi, K. and de Massy, M.R. and Ismail, M. and Reading, J.L. and Uddin, I. and Woolston, A. and Hatipoglu, E. and Oakes, T. and Rosenthal, R. and Peacock, T. and Ronel, T. and Noursadeghi, M. and Turati, V. and Furness, A.J.S. and Georgiou, A. and Wong, Y.N.S. and Ben Aissa, A. and Sunderland, M.W. and Jamal-Hanjani, M. and Veeriah, S. and Birkbak, N.J. and Wilson, G.A. and Hiley, C.T. and Ghorani, E. and Guerra-Assunção, J.A. and Herrero, J. and Enver, T. and Hadrup, S.R. and Hackshaw, A. and Peggs, K.S. and McGranahan, N. and Swanton, C. and Quezada, S.A. and Chain, B.
Abstract: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.
Keywords:Adoptive Immunotherapy, CD8-Positive T-Lymphocytes, Genetic Heterogeneity, Mutation, Non-Small-Cell Lung Carcinoma, T-Cell Antigen Receptors, Tumor-Infiltrating Lymphocytes
Source:Nature Medicine
Publisher:Nature Publishing Group
Page Range:1549-1559
Date:October 2019
Additional Information:Roland Schwarz is a member of the TRACERx Consortium. Erratum in Nat Med 26 (7): 1148.
Official Publication:https://doi.org/10.1038/s41591-019-0592-2
External Fulltext:View full text on PubMed Central
PubMed:View item in PubMed

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