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

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.