Abstract
Invariant natural killer T (iNKT) cells comprise a unique subset of lymphocytes that are primed for activation and possess innate NK-like functional features. Currently, iNKT cell-based immunotherapies remain in early clinical stages, and little is known about the ability of these cells to survive and retain effector functions within the solid tumor microenvironment (TME) long-term. In conventional T cells (TCONV), cellular metabolism is linked to effector functions and their ability to adapt to the nutrient-poor TME. In contrast, the bioenergetic requirements of iNKT cells – particularly those of human iNKT cells – at baseline and upon stimulation are not well understood; neither is how these requirements affect effector functions such as production of cytokines and cytolytic proteins. We find that unlike TCONV, human iNKT cells are not dependent upon glucose or glutamine for these effector functions upon stimulation with anti-CD3 and anti-CD28. Additionally, transcriptional profiling revealed that stimulated human iNKT cells are less glycolytic than TCONV and display higher expression of fatty acid oxidation (FAO) and adenosine monophosphate-activated protein kinase (AMPK) pathway genes. Furthermore, stimulated iNKT cells displayed higher mitochondrial mass and membrane potential relative to TCONV. Real-time Seahorse metabolic flux analysis revealed that stimulated human iNKT cells utilize fatty acids as substrates for oxidation more than stimulated TCONV. Together, our data suggest that human iNKT cells possess different bioenergetic requirements from TCONV and display a more oxidative metabolic program relative to effector TCONV. Importantly, iNKT cell-based immunotherapeutic strategies could co-opt such unique features of iNKT cells to improve their efficacy and longevity of anti-tumor responses.
Highlights
Invariant natural killer T cells comprise a subset of innate-like T lymphocytes with TCR specificity for glycolipid antigens presented by the monomorphic, MHC I-like molecule CD1d [1]. iNKT cells possess innate-like effector cell features, including rapid activation, cytokine secretion, and trafficking to tumor sites; as such, iNKT cells bridge innate and adaptive immune responses [2, 3]
A recent study suggested that mouse iNKT cells uptake less glucose than CD4+ T cells [31], suggesting that they may be less reliant on glucose metabolism
While new insights have begun to highlight the importance of cellular metabolism for sustained effector function and persistence of effector T cells within the tumor microenvironment (TME), these insights have not been extended to iNKT cells – human iNKT cells
Summary
Invariant natural killer T (iNKT) cells comprise a subset of innate-like T lymphocytes with TCR specificity for glycolipid antigens presented by the monomorphic, MHC I-like molecule CD1d [1]. iNKT cells possess innate-like effector cell features, including rapid activation, cytokine secretion, and trafficking to tumor sites; as such, iNKT cells bridge innate and adaptive immune responses [2, 3]. INKT cells possess innate-like effector cell features, including rapid activation, cytokine secretion, and trafficking to tumor sites; as such, iNKT cells bridge innate and adaptive immune responses [2, 3] The presence of both circulating and intratumoral iNKT cells predicts more favorable tumor prognosis and survival in patients with several solid and liquid tumors [reviewed in [4]], suggesting that these cells play central roles in cancer immunity. In order to better inform the design of iNKT cell-based solid tumor immunotherapies in the future, there is a great need to better understand the metabolic properties of iNKT cells and how these are linked to anti-tumor effector functions
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