Tumor monocyte content predicts immunochemotherapy outcomes in esophageal adenocarcinoma.

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. [Display omitted] • An EAC immunochemotherapy (ICI+CTX) trial: four weeks of ICI (ICI-4W), then ICI+CTX • A T/NK cell gene signature (INCITE) is upregulated in patients responding to ICI • High tumor monocyte content and mutational burden predict ICI+CTX outcomes • This biomarker combination also shows promise for EBV-/MSS gastric cancer Carroll et al. report that four weeks of immune checkpoint inhibitors is sufficient to induce tumor shrinkage in esophageal adenocarcinoma patients upregulating the "INCITE" gene signature. Integration of single-cell RNA sequencing and bulk RNA sequencing through deconvolution identified tumor monocyte content and tumor mutational burden as independent and complementary predictive biomarkers for immunochemotherapy. [ABSTRACT FROM AUTHOR]