Single cell genomics and immune responses to cancer therapies

Abstract

Increased tumour infiltrating lymphocytes (TILs) is correlated with improved clinical outcomes. We hypothesised high TILs comprised a distinct functional state. In breast cancer (BC), we showed TILs were significantly increased in primary compared to metastatic disease. Using single cell genomics, high TIL BC had increased CD8+ T cells with a resident memory T cell (TRM) differentiation. BC patients with high TRM gene signature expression and CD8+ T cells had improved progression free and overall survival. In a vaginal melanoma case study, we explored evolution of the melanoma and the patient immune responses. Using longitudinal samples, we investigated whether TRM were present and whether melanoma progression was associated with TRM dysfunction. TRM were the most tumour-responsive and were present in both metastases on the tumour margin. The TRM clonotypes were shared with other T cell clusters in the tumour and the peripheral blood. TRM responded to both melanoma differentiation antigens and a conserved neoantigen (mutated CDKN1C) across both metastatic sites and were significantly increased in the metastasis following anti-PD1 treatment. Finally, we revealed untreated BRAFmut primary, or metastatic melanoma had a distinct immune context to that of BRAFWT disease, providing new evidence to explain the difference in response to immunotherapy.