NKT cells of cancer patients and how models can inform therapeutic plans

Abstract

Multiple immune cells contribute to antitumor activity. Adaptive immune cells have specificity and amplified responses to repeated antigen, but require targeting to tumor to avoid excessive autoimmune effects. Innate elements can directly kill tumor cells, have specificity and even a form of memory, and can recruit adaptive responses, but have a finite spectrum of targeting ligands. Invariant natural killer T cells (iNKT) are a subset of innate-like CD1d-restricted T cells with roles in regulating immunity, including immune surveillance against certain pathogens and tumors. iNKT recognize lipid antigens presented by monomorphic MHC-like CD1d expressed by dendritic cells (DC) and other antigen presenting cells (APC) as well as many hemopoietic, prostate, and some other solid tissues and corresponding tumors. Studies of human cancer have revealed frequent and selective numerical and functional defects in iNKT, which correlate with progression, but are reversible in vitro (at least). iNKT can contribute to physiological antitumor responses in animal models. iNKT activation with αGalCer (as originally identified) and newer analogs promotes model tumor rejection and protection from metastasis. However, CD1d-restricted either (either "noninvariant" or iNKT) NKT can also suppress antitumor responses through regulatory cytokine(s). Defects of iNKT appear to be mediated by both intrinsic causes and by impaired stimulatory capacity of DC present in tumor microenvironment (TME). iNKT have great therapeutic potential. Although this potential has been limited to date, apparently by such iNKT defects, combinations such as αGalCer with IL-12 can reverse model defects. This review summarizes progress, pitfalls, and new opportunities to exploitation of NKT cells in cancer therapy.