Location of CD39+ T cell sub-populations within tumours predict differential outcomes in non-small cell lung cancer

Abstract

An improved mechanistic understanding of immunosuppressive pathways in NSCLC is important to develop novel diagnostic and therapeutic approaches. Here, we reveal that the prognostic significance of the rate limiting ectonucleotidases in adenosine production CD39 and CD73 requires knowledge of cell type specific expression and localisation within tumours. In a cohort of early treatment naive NSCLC patients, high stromal expression of CD39 and CD73 predicts poor outcome. CD39 expression amongst T cells identifies CD39+CD4+ Tregs which predict poor outcome and CD39+CD103+ CTL which confer a survival benefit if high densities are observed inside of the tumour nest. Bulk RNA Seq shows that the TME of NSCLC upregulates regulatory pathways in CD4+ T cells and exhaustion in CD8+ T cells. Analysis of single-cell RNASeq datasets illustrates that CD39+CD4+ Tregs are enriched in Treg signature gene sets, and CD39+CD103+ CTL show gene signatures indicative of an exhausted cytotoxic phenotype with an upregulated expression of CXCL13. Combined knowledge of patterns of distribution and location are required to understand the prognostic impact of CD39+ T cell populations in NSCLC. This study provides an improved understanding of the spatial and functional characteristics of CD39+ T cells and illustrates their significance to patient outcome.

Human effector CD8+ T cells with an activated and exhausted-like phenotype control tumour growth in vivo in a humanized tumour model

“… 48 Likewise, the abundance of intratumoral CD39 + CD8 + T cells displaying upregulated exhaustion markers has been shown to be prognostic for improved progression-free and overall survival in individuals with treatment-naïve early stage lung cancer. 64 Furthermore, PD-1 hi CD39 + CD8 + T cells correlated with improved survival in patients with endometrial cancer 47 and the signature of similar CD8 + T cells with increased TOX expression predicted survival in patients with breast cancer. 46 Recently, pre-existing exhausted-like tumour-reactive CD8 + T cells have been associated with favourable outcome to immunotherapy in head and neck cancer.…”

Human effector CD8+T cells with an exhausted-like phenotype control tumor growthin vivoin a humanized tumor model

“…Of note, CD39 + CD8 + T cells expressing high levels of PD-1 have been described to be enriched for tumor reactivity and clonal proliferation, predicting efficacy of immunotherapy in human lung cancer (46). Likewise, the abundance of intratumoral CD39 + CD8 + T cells displaying upregulated exhaustion markers has been shown to be prognostic for improved progression-free and overall survival in individuals with treatment-naïve early stage lung cancer (62). Furthermore, PD-1 hi CD39 + CD8 + T cells correlated with improved survival in patients with endometrial cancer (45) and the signature of similar CD8 + T cells with increased TOX expression predicted survival in patients with breast cancer (44).…”

Cancer-associated fibroblasts expressing fibroblast activation protein and podoplanin in non-small cell lung cancer predict poor clinical outcome

“…A TMA was constructed as previously described [30,31] from tumour resections from patients undergoing surgery for treatment of NSCLC with curative intent. Here a total of 163 cancer cores were available for staining.…”