Refining the role of dual checkpoint inhibition in advanced lung cancer: a single-cell approach

Immunotherapy has brought long-awaited progress in the treatment of an expanding array of cancer types. Specifically, anti-PD-1 immune checkpoint blockade (ICB) has become the backbone of first-line treatment of non-oncogene addicted advanced non-small cell lung cancer (NSCLC), with or without chemotherapy depending on PD-L1 expression level (based on KEYNOTE-024, KEYNOTE-089 and KEYNOTE-407). However, survival benefit is seen in a minority of unselected patients (20%), and current knowledge regarding molecular mechanisms of response or resistance to ICB is limited. This hampers adequate patient selection. The research team therefore previously set up an observational clinical trial (NCT04807114), using single-cell RNA-sequencing (scRNA-seq) to dissect the NSCLC tumor micro-environment prior to anti-PD-1 treatment and uncover immune characteristics that dictate response. The current PhD proposal builds upon this ongoing research project, but will focus on tackling an emerging clinical knowledge gap. Namely, based on results from CHECKMATE 9LA, the triple combination therapy of chemotherapy with anti-PD-1 Nivolumab and anti-CTLA-4 Ipilimumab will shortly be reimbursed as an alternative first-line treatment regimen. Patient selection for this triple combination treatment is of utmost importance, as the potential survival benefit must be weighed against the increased risk of severe immune-related adverse events. However, no predictive biomarkers are available. Hence, we will perform scRNA-seq of metastatic tumor-draining lymph nodes (TDLNs), as anti-CTLA-4 mainly acts in this compartment, before and during treatment. TDLNs are an understudied immunological niche, with scRNA-seq of TDLNs holding great promise to increase our understanding of how anti-CTLA-4 therapy modulates dendritic cell – T-cell interactions and how this impacts response to ICB.