AUTHOR=Shissler Susannah C. , Lee Michael S. , Webb Tonya J. 

TITLE=Mixed Signals: Co-Stimulation in Invariant Natural Killer T Cell-Mediated Cancer Immunotherapy

JOURNAL=Frontiers in Immunology

VOLUME=Volume 8 - 2017

YEAR=2017

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2017.01447

DOI=10.3389/fimmu.2017.01447

ISSN=1664-3224

ABSTRACT=Invariant natural killer T (iNKT) cells are an integral component of the immune system and play an important role in anti-tumor 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 PD-1.  Similar to conventional T cells, iNKT cells are influenced by the conditions of their activation.  Conventional T cells receive signals through 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 paper will review the background of iNKT cells and their co-stimulatory requirements for general function and in anti-tumor immunity.  We will explore the impact of monoclonal antibody administration for both blocking inhibitory pathways and engaging stimulatory pathways on iNKT cell-mediated anti-tumor immunity.  This review will highlight the incorporation of co-stimulatory molecules in anti-tumor dendritic cell (DC) vaccine strategies.  The use of co-stimulatory intracellular signaling domains in chimeric antigen receptors (CAR)-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.