Ghorani, Ehsan; (2022) Intratumour CD4 T cell differentiation skewing and loss of immune fitness in non-small cell lung cancer. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Cancer cells bear mutations that give rise to novel (neo-) antigens recognised by T cells of the immune system, but their capability to control tumour growth in untreated patients with clinically evident disease is limited. The importance of neoantigen directed immunity is demonstrated by the observation that tumour mutational burden (TMB) predicts immunotherapy outcome in non-small cell lung cancer (NSCLC). However, persistent antigen exposure can drive dysfunctional differentiation and negatively impact T cell function. CD4 T helper cells are key orchestrators of immunity in states of persistent antigen exposure, but whether they undergo a similar process within the tumour microenvironment and what drives it, are unknown. Here I integrated high dimensional flow cytometry, exome, bulk, T cell receptor (TCR) and single T cell RNA sequencing from patients with surgically resected NSCLC to explore these questions. I found that TMB and activated PD1+ regulatory T cell abundance associated with changes in the intratumour CD4 T cell differentiation landscape. This was characterised by what I have termed differentiation skewing - a reduced abundance of early differentiated cells with a CCR7+ central memory phenotype and TCF7+ progenitor-like transcriptional features, and gain of distinct PD1+ populations with high co-inhibitory and co-stimulatory receptor expression (CD57-ICOShiCTLA4+), markers of terminal differentiation (CD57+Eomes+) and transcriptional features of CD4 dysfunction. Sharing of TCR sequences between these populations is an indication of developmental pathways connecting these states and analysis of sequencing and cytometry data was compatible with TMB as a driver of the process. A validated gene signature of differentiation skewing was associated with worse outcomes in independent cohorts of patients with NSCLC and other cancer types, including patients enrolled to clinical trials of immunotherapy, suggesting the process marks a loss of immune fitness within the TME. Analysis of multi-source transcriptomic data sheds light on potential regulatory mechanisms and therapeutic targets.

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