Abstract
Invariant natural killer T cells (iNKTs) directly kill tumor cells and trans-activate the anti-tumor functions of dendritic cells (DC), natural killer (NK) cells, and T and B cells. As such, iNKTs serve as a powerful tool for use in cell-based cancer immunotherapy. iNKT cell activation commonly requires engagement of the invariant T cell receptor (iTCR) by CD1d presenting glycolipid antigens. However, transformed cells often down-regulate CD1d expression, which results in a reduction of iNKT cell anti-tumor functions. One approach to circumvent this critical barrier to iNKT cell activation is to develop an agonistic antibody that binds directly to the iTCR without the requirement for CD1d-mediated antigen presentation. To this end, we have characterized the iNKT cell stimulatory properties of NKTT320, a novel, recombinant, humanized, monoclonal antibody that binds selectively and with high affinity to human iTCRs. Strikingly, immobilized NKTT320 mediated robust iNKT cell activation (upregulation of CD25 and CD69) and proliferation (carboxyfluorescein succinimidyl ester (CFSE) dilution), as well as Th1 and Th2 cytokine production. Additionally, iNKTs stimulated by plate-bound NKTT320 exhibited increased intracellular levels of granzyme B and degranulation (exposure of CD107 on the cell surface). Furthermore, both soluble and immobilized NKTT320 induced iNKT cell-mediated activation of bystander immune cells, suggesting that this novel anti-iTCR antibody facilitates both direct and indirect iNKT cell cytotoxicity. These studies are significant, as they provide a framework by which iNKT cell anti-cancer functions could be enhanced for therapeutic purposes.
Highlights
Invariant natural killer T cells are unique, innate-type T lymphocytes that develop in the thymus and have characteristics of both conventional T cells and natural killer (NK) cells [1]
Incubation of Invariant natural killer T cells (iNKTs) with varying concentrations of the immobilized monoclonal antibody (mAb) increased the expression of activation markers CD25 and CD69, with an average of 4–6-fold increases in the mean fluorescence intensity (MFI)
INKT cell numbers are diminished in many cancer patients, and are often accompanied by functional defects, such as decreased proliferation and poor cytokine production [5,6,7,8]
Summary
Invariant natural killer T cells (iNKTs) are unique, innate-type T lymphocytes that develop in the thymus and have characteristics of both conventional T cells and natural killer (NK) cells [1]. Tumor cells often downregulate CD1d, and thereby evade iNKT cell recognition [21,22,23] To overcome this critical barrier, several novel approaches, including bi-specific fusion proteins and chimeric antigen receptor (CAR)-transduced iNKTs, have recently been tested in preclinical tumor models, where they have exhibited significant anti-tumor activity [24,25,26]. These approaches are limited by the number of known tumor antigens against which iNKTs may be targeted
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