ACP McElwain Prize winner

Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade

Andrew Furness, UCL Cancer Institute, London, UK

Regulation of T cell function represents a key obstacle to the successful clinical application of tumour immunotherapy. Antibody-mediated blockade of co-inhibitory immune checkpoint molecules seeks to address such regulation. Durable remissions and even cure has been observed in patients with advanced cancer, however, such responses are limited to a small fraction of treated patients. The identification of biomarkers predictive of response and resistance to therapy therefore remains an area of high scientific priority. Recent studies highlight the impact of the genomic landscape on anti-tumour immunity. Tumour-specific mutations may serve as neoantigens, eliciting T cell responses, and appear to be enriched in patients with advanced melanoma and non-small cell lung cancer (NSCLC) deriving benefit from CTLA-4 and PD-1 blockade respectively.
Genetic heterogeneity within single tumours is well described, however the impact of intra-tumour heterogeneity (ITH) upon the neoantigen landscape and anti-tumour immunity has remained unclear. Through parallel genomic and immunological approaches, we identified neoantigen-reactive CD8+ T cells in patients with early-stage NSCLC. Characterisation of these cellular subsets revealed high expression of co-inhibitory immune checkpoint molecules including PD-1. Analysis of clonal architecture demonstrated that all
identified T cell responses were directed against clonal neoantigens, present on every cancer cell. Clonal neoantigens were found to impact positively on overall survival in primary lung adenocarcinoma. Tumours with a high burden of clonal neoantigens displayed an inflamed phenotype, with high levels of CD8A, IFN-γ, STAT-1, PD-1, LAG-3 and PD-L1/2 gene expression. In keeping with these observations, sensitivity to CTLA-4 and PD-1 blockade in patients with advanced melanoma and NSCLC appeared enhanced in tumours enriched for clonal, but not subclonal neoantigens.
Heterogeneity in the neoantigen landscape may therefore influence immune surveillance. Clonal neoantigens, shared by all tumour cells, represent a key substrate for T cell recognition and an attractive target for adoptive cell-based and vaccination strategies which may hold promise to address the challenges of ITH.