7O - Deciphering the intra-tumoural T cell receptor repertoire in patients with NSCLC within the lung TRACERx study. (7O)

Date 08 December 2017
Event ESMO Immuno-Oncology Congress 2017
Session Proffered Paper session
Topics Colon Cancer
Gastrointestinal Cancers
Translational Research
Presenter Kroopa Joshi
Citation Annals of Oncology (2017) 28 (suppl_11): xi1-xi2. 10.1093/annonc/mdx712
Authors K. Joshi1, J.L. Reading1, M. Ismail2, T. Oakes2, R. Rosenthal3, I. Uddin2, M. Jamal-Hanjani3, N. McGranahan3, Y.N.S. Wong1, A.J. Furness1, A.B. Aissa1, M. Werner Sunderland1, A. Georgiou1, S. Veeriah3, J. Czyzewska-Khan3, T. Marafioti4, K. Peggs1, C. Swanton3, B.M. Chain2, S. Quezada1
  • 1Cancer Immunology Unit, UCL Cancer Institute, WC1E - DD/GB
  • 2Division Of Infection And Immunity, UCL, WC1E - BT/GB
  • 3Translational Cancer Therapeutics Laboratory, UCL Cancer Institute, WC1E - DD/GB
  • 4Department Of Cellular Pathology, UCLH, NW1 - BU/GB

Abstract

Background

Our group has previously demonstrated the importance of the clonality of cancer mutations in predicting overall survival in NSCLC and response to checkpoint blockade. Genomic analysis of the first 100 cases within the lung TRACERx study has shown an increased risk of recurrence or death associated with increased intratumoural heterogeneity. Conceivably, the level of mutational burden and genomic heterogeneity could be reflected in the adaptive anti-tumoural immune response in these patients.

Methods

Here, we report TCR sequencing data from multi-region tumour specimens and normal lung in patients within the lung TRACERx study with either genetically heterogeneous (high ITH) or homogenous (low ITH) NSCLC tumours.

Results

We found that the TCR repertoire in tumour specimens is distinct to that observed in normal lung with the majority of CDR3 sequences found to be unique to either compartment, suggestive of a repertoire of T cells spatially confined to the tumour microenvironment, possibly driven by the presence of tumour antigen. We observed a significantly lower degree of overlap in the TCR repertoire between matched normal tissue and tumour tissue compared to the TCR repertoire across multi-region tumour specimens. TCR repertoire heterogeneity was found to reflect neoantigen heterogeneity; we found a significantly higher degree of TCR repertoire overlap, as assessed by the Jaccard index of the 100 most abundant TCRs, in patients with low ITH tumours as compared to high ITH tumours. Moreover, we observed a correlation between TCR clonality and neoantigen load in patients with low ITH tumours.

Conclusions

Taken together, these findings demonstrate a heterogeneous spatial distribution of tumour infiltrating lymphocytes among patients with NSCLC. Theoretically TCR clones, present across multiple regions of the tumour may expand in response to common neoantigens found in all cancer cells and efforts are currently underway to determine the antigen specificity of such TCRs. The observations described are indicative of a dynamic intra-tumoural T cell response that may be accounted for by differences in the genetic heterogeneity in the mutational and predicted neoantigen burden observed in NSCLC.

Clinical trial identification

Funding

None

Disclosure

K. Peggs, S. Quezada: Founder of Achilles Therapeutics. C. Swanton: Receipt of grants/research supports: Pfizer; Receipt of honoraria or consultation fees: Roche Ventana, Celgene, Pfizer, Novartis; Stock shareholder: Grail, Epic Biosciences, Apogen Biotechnologies, Achilles Therapeutics. All other authors have declared no conflicts of interest.