Tumor-Infiltrating Natural Killer Cells

Abstract

Because of their potent antitumor activity and their proinflammatory role, natural killer (NK) cells are at the forefront of efforts to develop immuno-oncologic treatments. NK cells participate in immune responses to tumors by killing target cells and producing cytokines. However, in the immunosuppressive tumor microenvironment, NK cells become dysfunctional through exposure to inhibitory molecules produced by cancer cells, leading to tumor escape. We provide an overview of what is known about NK tumor infiltration and surveillance and about the mechanisms by which NK cells become dysfunctional. SIGNIFICANCE: The functions of tumor-infiltrating NK cells may be impaired. This review aims to describe the various mechanisms by which tumors alter NK-cell functions.

Figure 1. Comparison of NK cell immune infiltration and CD8 T-cell infiltration in various cancer tissues.

RNA data from The Cancer Genome Atlas were analyzed by selecting a set of significantly differentially expressed genes as the NK-cell and CD8 T-cell signatures. The NK-cell signature was composed of the following genes: CD160, CD244, CHST12, CST7, GNLY, IL18RAP, IL2RB, KLRC1, KLRC3, KLRD1, KLRF1, PRF1, XCL2, and NCR1. The CD8 T-cell signature was composed of the following genes: CD3D, CD3E, CD8A, CD8B, KLRC1, KLRK1, GZMH, and CCL5. Expression values were summed to obtain the NK score and the CD8 T score. Cancer tissues are ranked by increasing median of log2-normalized expression. ACC, adrenocortical carcinoma; BLCA, bladder urothelial carcinoma; BRCA, breast invasive carcinoma; CESC, cervical squamous cell carcinoma and endocervical adenocarcinoma; CHOL, cholangiocarcinoma; COAD, colon adenocarcinoma; DLBC, lymphoid neoplasm diffuse large B-cell lymphoma; ESCA, esophageal carcinoma; GBM, glioblastoma multiforme; HNSC, head and neck squamous cell carcinoma; KICH, kidney chromophobe; KIRC, kidney renal clear cell carcinoma; KIRP, kidney renalpapillary cell carcinoma; LAML, acute myeloid leukemia; LGG, brain lower grade glioma; LIHC, liver hepatocellular carcinoma; LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma; MESO, mesothelioma; OV, ovarian serous cystadenocarcinoma; PAAD, pancreatic adenocarcinoma; PCPG, pheochromocytoma and paraganglioma; PRAD, prostate adenocarcinoma; READ, rectum adenocarcinoma; SARC, Sarcoma; SKCM, skin cutaneous melanoma; STAD, stomach adenocarcinoma; TGCT, testicular germ cell tumors; THCA, thyroid carcinoma; THYM, thymoma; UCEC, uterine corpus endometrial carcinoma; UCS, uterine carcinosarcoma; UVM, uveal melanoma.

Figure 2. Mechanisms involved in NK cell dysfunction in the tumor bed.

Tumor cells can modify the extracellular environment by producing immunosuppressive cytokines, such as TGFβ, which decrease NK-cell functionality and infiltration. The tumor cells can also affect NK functionality by promoting hypoxic conditions leading to an activation of the intracellular protein mTOR-DRP1 causing mitochondrial fragmentation in the NK cell. Mesenchymal stem cells (MSC) and tumor cells produce prostaglandin-E2 (PGE2), which decreases NK cytotoxicity. Regulatory T cells (Treg) can directly suppress NK-cell function or indirectly influence NK-cell inhibition by secreting IL10 and TGFβ. Myeloid-derived suppressor cells (MDSC) can inhibit NK-cell ADCC via the secretion of nitric oxide (NO). Tumor cell–secreted IL6 and IL8 impair the activity and function of NK cells via STAT3, suppressing expression of the NK cell–activating receptors NKp30 and NKG2D. In many human tumors, a downregulation of the expression of the activating receptors NKp46, NKp30, NKG2D, DNAM1, and CD16 has been observed on NK cells, with a direct negative impact on NK-cell activation and antitumor function. Moreover, tumor cells have been found to overproduce and shed the ligands of these activating receptors (e.g., NKp30 ligand B7-H6 and NKG2D ligands MICA and MICB), inducing an inhibition of activating signaling pathways. The metalloprotease ADAM17 expressed on the surface of tumor cells in addition to participating in the shedding of B7-H6 is also able to induce the cleavage of the activating CD16. Tumor cells are able to attract platelets, which in turn promote the release of NK2GDL and TGFβ, contributing to the suppression of NK-cell function. Tumor cells can also overexpress ligands (e.g., CD155, PD-L1, and HLA-E) of NK inhibitory receptors and increase the expression of some of these receptors, such as TIGIT, PD-1, and NKG2A, leading to alterations of the function of infiltrating NK cells.