Tumor monocyte content predicts immunochemotherapy outcomes in esophageal adenocarcinoma

Cancer Cell. 2023 Jul 10;41(7):1222-1241.e7. doi: 10.1016/j.ccell.2023.06.006.

Abstract

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.

Keywords: cell type deconvolution; esophageal cancer; immune checkpoint inhibitors; immune priming; immunochemotherapy; molecular profiling; predictive biomarkers; single-cell RNA-sequencing atlas; tumor associated monocytes; tumor mutational burden.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma* / drug therapy
  • Adenocarcinoma* / genetics
  • Esophageal Neoplasms* / drug therapy
  • Esophageal Neoplasms* / genetics
  • Humans
  • Immunotherapy
  • Monocytes
  • Stomach Neoplasms*

Supplementary concepts

  • Adenocarcinoma Of Esophagus