Targeting Natural Killer T Cells in Solid Malignancies

Abstract

Natural killer T (NKT) cells are a unique subset of lymphocytes that recognize lipid antigens in the context of the non-classical class I MHC molecule, CD1d, and serve as a link between the innate and adaptive immune system through their expeditious release of cytokines. Whereas NKT have well-established roles in mitigating a number of human diseases, herein, we focus on their role in cancer. NKT cells have been shown to directly and indirectly mediate anti-tumor immunity and manipulating their effector functions can have therapeutic significances in treatment of cancer. In this review, we highlight several therapeutic strategies that have been used to harness the effector functions of NKT cells to target different types of solid tumors. We also discuss several barriers to the successful utilization of NKT cells and summarize effective strategies being developed to harness the unique strengths of this potent population of T cells. Collectively, studies investigating the therapeutic potential of NKT cells serve not only to advance our understanding of this powerful immune cell subset, but also pave the way for future treatments focused on the modulation of NKT cell responses to enhance cancer immunotherapy.

Keywords: CD1d; NKT cells; cancer immunotherapy.

Figure 1

CD1D expression in different cancer types compared to corresponding healthy tissues. NKT cells can recognize and mediate cytolysis, thus CD1d-expression on malignant cells is an area of active investigation. It is thought that higher expression of CD1d leads to in higher tumor cell killing. Thus, several tumors have been shown to downregulate CD1d expression, perhaps in order to escape NKT cell-mediated immunosurveillance, or these data reflect a positive selection pressure for CD1d-low tumor cells. cBioPortal was used to investigate CD1D expression in different cancer types available in the TCGA database [64]. Data shown represents CD1d mRNA expression z scores relative to normal samples. (A) Median levels of CD1D is shown and 0 (no change) is indicated by a red line. (B) Each patient sample is indicated by a blue circle. BLCA = bladder urothelial carcinoma; BRCA = breast invasive carcinoma; CHOL = cholangiocarcinoma; COAD = colon adenocarcinoma; ESCA = Esophageal carcinoma; HNSC = Head and Neck squamous cell carcinoma; KICH = Kidney chromophobe; KIRC = Kidney clear cell carcinoma; KIRP = Kidney renal papillary cell carcinoma; LIHC = Liver hepatocellular carcinoma; LUAD = lung adenocarcinoma; LUSC = lung squamous cell carcinoma; PRAD = Prostate adenocarcinoma; READ = Rectum adenocarcinoma; STAD = Stomach adenocarcinoma; HCA = Thyroid carcinoma; UCEC = Uterine Corpus Endometrial Carcinoma.

Figure 2

Targeting invariant natural killer T (iNKT) cells in solid tumors. Many strategies are being employed to harness the power of NKT cells in cancer immunotherapy. Treatment with α-GalCer-pulsed APC has been shown to result in antitumor immune responses, particularly in lung and head and neck cancers. Cell based therapeutics such as CAR-NKT and HSC-iNKT cells have shown efficacy in preclinical models. In addition, there are several reports investigating the direct modulation of NKT cells using BiTEs and α-GalCer-based therapy. Taken together, these studies demonstrate the feasibility of targeting NKT cells for cancer immunotherapy and present innovative strategies that can be employed to increase our understanding of this important population of T cells.