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Oesophageal cancer is the sixth leading cause of cancer mortality worldwide, and the incidence of oesophageal adenocarcinoma has been climbing at a relatively swift clip over the past 40 years. Survival times for inoperable or metastatic forms of the cancer range from 6 to 12 months.
Led by Professor Xin Lu, Professor of Cancer Biology and Director of the Ludwig Institute for Cancer Research at the Nuffield Department of Medicine, and former graduate student Thomas Carroll and published in the current issue of the journal Cancer Cell, the study also shows that the degree to which a tumour's malignant cells are mutated is similarly predictive of survival outcomes. Further, combining measurement of tumour mutational burden (TMB) and tumour monocyte content (TMC) better predicts treatment response than either measurement alone. This suggests that the combined measurement is a potential biomarker for the selection of patients likely to benefit from immunochemotherapy.
"Some cancer patients respond to treatment while some do not, and still others respond only partially," said Lu. "The challenge is to understand why certain people fall into each category and identify the molecular bases of their heterogeneous responses."
A clinical trial launched in 2015 by Ludwig Oxford offered a unique opportunity to address this challenge. The 35 patients with inoperable oesophageal adenocarcinoma enrolled in this trial, unlike those in many others, received four weeks of immunotherapy with immune checkpoint inhibitors (ICI) alone (either anti-PD-L1, or anti-PD-L1 and anti-CTLA-4) before undergoing 18 weeks of combination immunochemotherapy.
Both healthy and cancerous biopsies were collected from the patients at multiple time points and from multiple sites over the course of their treatment. The researchers then performed single cell RNA sequencing (scRNA-seq) on 65,000 cells from a subset of the clinical trial patients to generate a detailed cellular atlas of the upper gastrointestinal tract, which served as a reference map of all the cell types that can be found in oesophageal cancers.
Due to technical and other challenges associated with scRNA-seq—which analyses the RNA output of individual cells—such analysis was only performed on 8 of the 35 EAC patients in the clinical trial. However, the biopsies of all patients underwent bulk RNA sequencing, a much more cost-effective alternative.
The trial was supported by grants from Cancer Research UK Centres Network Accelerator Award, Experimental Cancer Medicine Centre, AstraZeneca UK Ltd and National Institute for Health and Care Research (NIHR) Oxford Biomedical Research Centre.