Abstract
Invariant natural killer T (iNKT) cells are an integral component of the immune system and play an important role in antitumor immunity. Upon activation, iNKT cells can directly kill malignant cells as well as rapidly produce cytokines that stimulate other immune cells, making them a front line defense against tumorigenesis. Unfortunately, iNKT cell number and activity are reduced in multiple cancer types. This anergy is often associated with upregulation of co-inhibitory markers such as programmed death-1. Similar to conventional T cells, iNKT cells are influenced by the conditions of their activation. Conventional T cells receive signals through the following three types of receptors: (1) T cell receptor (TCR), (2) co-stimulation molecules, and (3) cytokine receptors. Unlike conventional T cells, which recognize peptide antigen presented by MHC class I or II, the TCRs of iNKT cells recognize lipid antigen in the context of the antigen presentation molecule CD1d (Signal 1). Co-stimulatory molecules can positively and negatively influence iNKT cell activation and function and skew the immune response (Signal 2). This study will review the background of iNKT cells and their co-stimulatory requirements for general function and in antitumor immunity. We will explore the impact of monoclonal antibody administration for both blocking inhibitory pathways and engaging stimulatory pathways on iNKT cell-mediated antitumor immunity. This review will highlight the incorporation of co-stimulatory molecules in antitumor dendritic cell vaccine strategies. The use of co-stimulatory intracellular signaling domains in chimeric antigen receptor-iNKT therapy will be assessed. Finally, we will explore the influence of innate-like receptors and modification of immunosuppressive cytokines (Signal 3) on cancer immunotherapy.
Highlights
This review focuses on the importance of Signal 2 for type I Invariant natural killer T (iNKT) cell activation and function in antitumor immunity
This immunotherapy generates a memory immune response. Another group designed a therapy called NKTMab that includes α-4-1BB, α-DR5, and α-GalCer or α-C-GalCer. This combination immunotherapy causes effective rejection of 4T1 breast cancer tumors in Balb/c mice that is dependent on CD4+ T cells, cytotoxic T lymphocytes (CTLs), iNKT cells, and IFN-γ, and they found that α-C-GalCer was more effective in a wider range of concentrations [89]
A study later conducted by Tian et al showed that stimulation with the combination of CD1d, CD86, 4-1BBL, and OX40L resulted in the greatest production of Th1 type cytokines by human CD19-specific CHIMERIC ANTIGEN RECEPTORS (CARs)-iNKT cells containing a 4-1BB costimulatory domain [104]
Summary
Progression of cancer to the stage of diagnosis indicates that the cancer has already undergone extensive immunoediting and has proceeded to the immune escape phase of immunosurveillance. While checkpoint inhibitors have side effects such as autoimmunity, agonistic monoclonal antibodies against stimulatory co-receptors can cause rampant, destructive immune activation—making researchers more cautious with their use Two such agonists, against members of the TNFRSF, have been explored in conjunction with iNKT cell immunotherapy: 4-1BB and GITR. In a mouse model of B cell lymphoma, treatment with α-GalCer-loaded, irradiated tumor cells and α-4-1BB increases overall survival and tumor-free survival dependent on IFN-γ and KLRG1+ CTLs [88] This immunotherapy generates a memory immune response. Another group designed a therapy called NKTMab that includes α-4-1BB, α-DR5, and α-GalCer or α-C-GalCer (a modified version of α-GalCer known to skew the iNKT cell response to Th1) This combination immunotherapy causes effective rejection of 4T1 breast cancer tumors in Balb/c mice that is dependent on CD4+ T cells, CTLs, iNKT cells, and IFN-γ, and they found that α-C-GalCer was more effective in a wider range of concentrations [89]. Treatment regimens that combine iNKT cell activation and checkpoint blockade or agonistic antibody treatments hold promise for the future
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