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Proteogenomic integration of single-cell RNA and protein analysis identifies novel tumour-infiltrating lymphocyte phenotypes in breast cancer

ABSTRACT: High-throughput single-cell RNA sequencing (scRNA-Seq) has become a routine platform for the dissection of solid tumours into their cellular components. The development of methods to incorporate detection of cellular protein epitopes via barcoded antibodies has enabled advances in immunophenotyping, but its application to investigating tissue immunology has been limited. We applied joint single cell RNA and epitope analysis to a cohort of 6 breast cancer samples to improve resolution of the tumour microenvironment (TME). We detect cell types unidentifiable by analysis of RNA or protein alone, and reveal novel markers for resting and activated tissue infiltrating lymphocytes (TILs). We further identify two distinct states of activated CD4+ T follicular helper (Tfh) cells in breast cancers – one associated with markers of tissue residency and exhaustion (CD103+ Tfh), and a previously-undescribed phenotype marked by the expression of IGFL2 and NMB (IGFL2+ Tfh). The two Tfh cell subsets occupy distinct TME niches, with CD103+ Tfh cells uniquely co-localizing with and signalling to macrophages. This Tfh cell stratification is clinically important, as the increased ratio of CD103 Tfh to IGFL2+ Tfh cells associates with improved disease outcome and response to checkpoint immunotherapy. Collectively, we provide a framework for improved phenotyping of TILs and showcase how proteogenomics more robustly catalogues the emergence of novel cellular states with clinical significance in tissue contexts such as the TME.

ORGANISM(S): Homo sapiens

PROVIDER: GSE199219 | GEO | 2024/06/30

REPOSITORIES: GEO

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