Switching Invariant Natural Killer T (iNKT) Cell Response from Anticancerous to Anti-Inflammatory Effect: Molecular Bases

Abstract

Since the discovery in 1995 of α-galactosylceramide 1 (α-GalCer), also known as KRN7000,1 hundreds of compounds have been synthesized in order to activate invariant natural killer T (iNKT) cells. Such keen interest for this lymphocyte cell type is due to its ability to produce different cytokines that bias the immune response toward a Th1 or Th2 profile. Thus, an understanding of the immune polarization mechanism via iNKT activation may pave the way toward new therapeutics in various domains including cancer and infectious and autoimmune diseases. In this review, we propose an up-to-date analysis of iNKT activators associated with a structure-activity relationship (SAR) study aimed at complementing available reviews by highlighting molecular bases for a selective immune response.

Dual Modifications of α-Galactosylceramide Synergize to Promote Activation of Human Invariant Natural Killer T Cells and Stimulate Anti-tumor Immunity

“…A major issue in this regard is the tendency for KRN7000 to elicit high levels of both T helper 1 (Th1) and Th2 associated cytokines, which may have directly conflicting activities leading to ineffective and unpredictable immune responses. This problem has been addressed through the development of structural analogues of KRN7000 that stimulate i NKT cell responses that are more biased toward purely Th1 or Th2 cytokine predominance (Laurent et al, 2014). In general, analogues that bias toward interferon-γ (IFNγ) and other Th1 type cytokines following i NKT cell activation have been associated with favorable therapeutic effects in mouse models of cancer and infectious diseases (Kopecky-Bromberg et al, 2009; Schmieg et al, 2003), whereas Th2-biasing analogues may be more suitable for treatment of autoimmune or inflammatory conditions (Forestier et al., 2007; Miyamoto et al, 2001).…”

“…In general, analogues that bias toward interferon-γ (IFNγ) and other Th1 type cytokines following i NKT cell activation have been associated with favorable therapeutic effects in mouse models of cancer and infectious diseases (Kopecky-Bromberg et al, 2009; Schmieg et al, 2003), whereas Th2-biasing analogues may be more suitable for treatment of autoimmune or inflammatory conditions (Forestier et al., 2007; Miyamoto et al, 2001). Thus, it is well recognized that identifying ligands that selectively elicit Th1 or Th2 cytokines will likely be crucial for effective therapeutic applications of i NKT cell activation (Cerundolo and Salio, 2007; Laurent et al, 2014). …”

Synthesis and biological activities of C-glycosides of KRN 7000 with novel ceramide residues

“…The most well-studied glycolipid antigen is α-galactosylceramide (α-O-GalCer), also called KRN 7000, which has been tested in several mouse models of disease and in a limited number of human trials. 9,10,11,12 However, clinical applications of KRN 7000 have been stymied; the consensus of the immunology community is that it is handicapped by its inability to induce a clear Th1/Th2 cytokine bias. In this context C - KRN 7000, the C -glycoside analog in which the glycoside oxygen is replaced with a “CH 2 ”, emerged as a benchmark Th1 biased molecule in mice, inducing high levels of IFN-γ and IL-12 with negligible levels of IL-4.…”

The Crotylation Way to Glycosphingolipids: Synthesis of Analogues of KRN7000

“…In this context the synthesis and cytokine profiling of novel diverse analogues of KRN7000 has attracted much attention. 3 The polar part of the sphingosine residue has come under close scrutiny as subtle alterations in this segment have resulted in very different Th1/Th2 profiles. This behavior may be linked to the intimate interactions of this region within the glycolipid-CD1d-TCR ternary complex.…”