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

Serial Stimulation of Invariant Natural Killer T Cells with Covalently Stabilized Bispecific T-cell Engagers Generates Antitumor Immunity While Avoiding Anergy

“…In contrast, the relatively low numbers of iNKT cells in normal humans, and their further reduction and loss of function in many cancer patients (11,51), suggest that iNKT cell selective BiTEs are likely to be better tolerated, albeit less potent than more broadly acting T cell engagers. In this regard, it is encouraging that strong anti-tumor effects with iNKT cell engaging BiTEs were seen in our experiments with human CD1d knock-in mice, despite their low numbers of iNKT cells (37). These effects could potentially be amplified by combining iNKT cell selective conjugated BiTEs with strategies for increasing iNKT cell numbers and function, such as adoptive cell therapy for engineering of chimeric antigen receptor expressing iNKT cells (9,52).…”

“…7). The latter represent a potentially more accurate model for translational studies, since they closely resemble humans with regard to numbers of iNKT cells and the strength of responses to iNKT cell activators (21,37). Animals implanted with subcutaneous MC38-huHER2 tumors received three weekly i.v.…”

6″-Modifed α-GalCer-peptide conjugate vaccine candidates protect against liver-stage malaria

“…These responses can involve several T cell subsets, including two that recirculate around the body termed central memory T (T CM ) and effector memory T (T EM ) cells and a subset that resides permanently within tissues, termed resident memory T (T RM ) cells. While T RM cells can be found in a number of tissues, those localised in the liver are crucial for controlling liver-stage infection by Scheme 3 Synthetic route to 6 00 -deoxy-6 00 -thio-a-GalCer ( 23) and its pro-adjuvant form (24).…”

“…1), which is considered non-essential for binding of the CD1d:a-GalCer complex to the TCR. 14 Previously reported 6 00 -modified a-GalCer analogues include the amino, 19 azido, 20 thio, 21 hydro (deoxy), 22 and uronic acid 23 derivatives, which have been further modified to produce a range of ether, 19 ester, 24 amido, [25][26][27][28][29] carbamoyl, 26 carbamido, 27 triazole, 20,30-32 disulfide 21 and thioether 21 analogues, many of which display potent immunostimulatory activities that are biased for either a Th1 19,20,22,23,26,27,30,32 or Th2 19,20,25 response compared to a-GalCer. Notable among these 6 00 -modified a-GalCer analogues are ABX196 and PBS-57, both of which are 6 00 -NHAc derivatives with disparate N-acyl ceramide chains.…”

Gut Microbiota-Derived Unconventional T Cell Ligands: Contribution to Host Immune Modulation

“…Experimental findings from one murine model may not always be applicable to human diseases. One possible way to address this is to use humanized system, as shown in the case of transgenic mice with humanized type I NKT cells (116,117).…”