The Regulatory Role of Invariant NKT Cells in Tumor Immunity

Abstract

Invariant natural killer T (iNKT) cells are a unique population of T lymphocytes, which lie at the interface between the innate and adaptive immune systems, and are important mediators of immune responses and tumor surveillance. iNKT cells recognize lipid antigens in a CD1d-dependent manner; their subsequent activation results in a rapid and specific downstream response, which enhances both innate and adaptive immunity. The capacity of iNKT cells to modify the immune microenvironment influences the ability of the host to control tumor growth, making them an important population to be harnessed in the clinic for the development of anticancer therapeutics. Indeed, the identification of strong iNKT-cell agonists, such as a-galactosylceramide (a-GalCer) and its analogues, has led to the development of synthetic lipids that have shown potential in vaccination and treatment against cancers. In this Masters of Immunology article, we discuss these latest findings and summarize the major discoveries in iNKT-cell biology, which have enabled the design of potent strategies for immune-mediated tumor destruction.Cancer Immunol Res; 3(5); 425-35. Ó2015 AACR. Disclosure of Potential Conflicts of InterestNo potential conflicts of interest were disclosed. Editor's DisclosuresThe following editor(s) reported relevant financial relationships. G. Dranoff-None. CME Staff Planners' DisclosuresThe members of the planning committee have no real or apparent conflicts of interest to disclose. Learning ObjectivesResearch on the fundamental aspects of ab T-cell receptor (TCR) structure and function has informed infectious disease and oncology disciplines about the nature of cognate antigen recognition by the T-cell adaptive immune system. This information, in turn, will lead to effective development of CD8 T cell-based vaccines for preventive and immunotherapeutic purposes. Upon completion of this activity, the participant should gain a basic knowledge of the molecular structure of the ab TCR and the mechanobiology that allows a TCR to recognize a distinct foreign peptide among a myriad of antigens bound to the major histocompatibility complex with the required sensitivity and specificity for host protection.

Larger number of invariant natural killer T cells in PBSC allografts correlates with improved GVHD-free and progression-free survival

“…Indeed, during immunosurveillance, iNKTs can recognize endogenous lipids presented by CD1d molecules on tumors cells and subsequently eliminate tumor cells directly through iNKT-mediated lysis. 8 Thus, iNKTs have been shown to be protective in the antitumor immune response to B-cell lymphoma in a CD1d-dependent manner. 30 Of note, CD1d is preferentially expressed in hematopoietic cells, 31 and hematologic malignancies retain this expression.…”

“…5 Chaidos et al focused on invariant natural killer T cells (iNKTs), 6 a regulatory cell population implicated in immune tolerance and tumor surveillance. 7,8 They reported that the use of PBSC graft with fewer CD4 2 iNKTs was associated with an increased risk of acute GVHD (aGVHD). 6 Similarly, Rezvani et al evaluated regulatory T cells (Tregs) within the PBSC graft 9 and reported that patients who received allo-SCT with a PBSC graft that contained lower absolute number of Tregs were associated with a greater risk of developing aGVHD.…”

CD62L+ NKT cells have prolonged persistence and antitumor activity in vivo

“…The potential importance of NKTs for tumor immunity and immunotherapy has been demonstrated in multiple models of cancer in mice and in early-stage clinical trials in cancer patients (5)(6)(7)(8)(9)(10). In contrast to T cells, NKTs effectively traffic to the tumor site and can mediate antitumor responses via either direct killing of CD1d + tumor cells, inhibition of tumor-supportive macrophages, or transactivation of NK cells (11).…”

Exploring the functions of nonclassical MHC class Ib genes in Xenopus laevis by the CRISPR/Cas9 system

“…Due to their critical regulatory roles in immunity, class Ib and interacting iT cells such as iNKT and MAIT cells have emerged as suitable therapeutic targets against viral, microbial, and parasitic infections, autoimmune and allergic diseases, as well as malignant neoplastic growths (Fernandez et al, 2014; Juno et al, 2012; Macho-Fernandez and Brigl, 2015; McEwen-Smith et al, 2015; Robertson et al, 2014; Skold and Behar, 2003; Subleski et al, 2011). However, the clinical implementation of class Ib- and iT cell-based therapies is still far from realization and requires a deeper and more comprehensive understanding of the biology of this a system.…”