Single-cell RNA sequencing (scRNA-seq) techniques offer a novel approach to exploring the heterogeneity of cancers. These techniques have undergone rapid development over the past decade. One such innovation is cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq). This approach can connect transcriptomics and surface proteomics at the single-cell level. We applied CITE-seq to chronic lymphocytic leukaemia (CLL) patient samples to answer the clinical question of how the microenvironment plays a role in venetoclax resistance. CLL is the most common type of adult leukaemia in western countries. The BCL2-inhibitor venetoclax shows remarkable clinical efficiency in treating patients with CLL. However, the disease relapses in most patients after years of venetoclax monotherapy. Among patients with the relapsed disease, multiple sub-clones harbouring distinct mechanisms of resistance often co-exist. Therefore, understanding the heterogeneity of CLL is critical to addressing the challenge of drug resistance and disease relapse.
In this seminar, I will present my work on applying CITE-seq to patient lymph node samples to identify the potential mechanisms of venetoclax resistance induced by the microenvironment. Specifically, I observed that T-cell exhaustion was associated with the emergence of venetoclax resistance in CLL patients. Therefore, I investigated the impact of venetoclax on the immune systems of patients with solid tumours who received the treatment to explore the rationality of combining venetoclax with immunotherapies. In addition, I will also discuss my work in developing new methods for isoform detection and mutation calling at single-cell resolution.