Tumor monocyte content predicts immunochemotherapy outcomes in esophageal adenocarcinoma.
Carroll TM., Chadwick JA., Owen RP., White MJ., Kaplinsky J., Peneva I., Frangou A., Xie PF., Chang J., Roth A., Amess B., James SA., Rei M., Fuchs HS., McCann KJ., Omiyale AO., Jacobs B-A., Lord SR., Norris-Bulpitt S., Dobbie ST., Griffiths L., Ramirez KA., Ricciardi T., Macri MJ., Ryan A., Venhaus RR., Van den Eynde BJ., Karydis I., Schuster-Böckler B., Middleton MR., Lu X., LUD2015-005 Project Team None.
For inoperable esophageal adenocarcinoma (EAC), identifying patients likely to benefit from recently approved immunochemotherapy (ICI+CTX) treatments remains a key challenge. We address this using a uniquely designed window-of-opportunity trial (LUD2015-005), in which 35 inoperable EAC patients received first-line immune checkpoint inhibitors for four weeks (ICI-4W), followed by ICI+CTX. Comprehensive biomarker profiling, including generation of a 65,000-cell single-cell RNA-sequencing atlas of esophageal cancer, as well as multi-timepoint transcriptomic profiling of EAC during ICI-4W, reveals a novel T cell inflammation signature (INCITE) whose upregulation correlates with ICI-induced tumor shrinkage. Deconvolution of pre-treatment gastro-esophageal cancer transcriptomes using our single-cell atlas identifies high tumor monocyte content (TMC) as an unexpected ICI+CTX-specific predictor of greater overall survival (OS) in LUD2015-005 patients and of ICI response in prevalent gastric cancer subtypes from independent cohorts. Tumor mutational burden is an additional independent and additive predictor of LUD2015-005 OS. TMC can improve patient selection for emerging ICI+CTX therapies in gastro-esophageal cancer.