Low Abundance of Cytotoxic Natural Killer Cells in Peritoneal Metastasis from Appendiceal Adenocarcinoma Suggests Tumor Immune Escape.

Abstract

Natural killer (NK) cells are a principal component of the body's innate immune response to both primary and metastatic cancer.¹ In recent years, NK cells have been heavily investigated as both therapeutic targets and as adoptive cell therapies for the treatment of cancer, with the majority of prior in-human clinical investigation of NK cell therapies focusing on soluble blood cancers.² Both human and animal studies have demonstrated that robust NK cell function facilitates improved control of tumors in the gastrointestinal tract, including gastrointestinal stromal tumor, gastric, and colorectal cancer.¹ Previous work has not specifically examined the role of NK cells in either localized or metastatic appendiceal adenocarcinoma (AA), a molecularly distinct gastrointestinal tumor that has recently been increasing in incidence.³ Here, we assess the role of NK cells in AA by analyzing single-cell RNA sequencing (scRNA-seq) data from NK cells recovered from tumors of peritoneal metastasis of appendiceal adenocarcinoma (PMAA). We demonstrate that PMAA-infiltrating NK cells express a transcriptional program consistent with cell exhaustion, with only a small minority of NK cells expressing a classical cytotoxic phenotype. These findings suggest NK cell functional rescue as a possible strategy for the treatment of AA.