Abstract
Invariant natural killer T (iNKT) cells are a subset of lymphocytes with immune regulatory activity. Their ability to bridge the innate and adaptive immune systems has been studied using the glycolipid ligand α-galactosylceramide (αGC). To better harness the immune adjuvant properties of iNKT cells to enhance priming of antigen-specific CD8+ T cells, we encapsulated both αGC and antigen in a Clec9a-targeted nanoemulsion (TNE) to deliver these molecules to cross-presenting CD8+ dendritic cells (DC). We demonstrate that, even in the absence of exogenous glycolipid, iNKT cells supported the maturation of CD8α+ DCs to drive efficient cross-priming of antigen-specific CD8+ T cells upon delivery of Clec9a/OVA-TNE. The addition of αGC to the TNE (Clec9a/OVA/αGC) further enhanced activation of iNKT cells, NK cells, CD8α+ DCs, and polyfunctional CD8+ T cells. When tested therapeutically against HPVE7-expressing TC-1 tumors, long-term tumor suppression was achieved with a single administration of Clec9a/E7 peptide/αGC TNE. Antitumor activity was correlated with the recruitment of mature DCs, NK cells, and tumor-specific effector CD8+ T cells to the tumor-draining lymph node and tumor tissue. Thus, Clec9a-TNE codelivery of CD8+ T-cell epitopes with αGC induces alternative helper signals from activated iNKT cells, elicits innate (iNKT, NK) immunity, and enhances antitumor CD8+ T-cell responses for control of solid tumors.
Highlights
Invariant natural killer T cells are a subset of preactivated innate immune cells that possess markers of both NK and T cells and play a role in cancer immunity
We reported that cationic Clec9a antigen–targeted nanoemulsions (TNE) carrying whole antigen can promote cross-priming of antigen-specific CD8þ T cells through CD4þ T cell–mediated induction of IFNa and CD40 signaling, resulting in tumor suppression [23]
We investigated whether Clec9a/OVA TNE activates Invariant natural killer T (iNKT) cells and whether iNKT cells contribute to the self-adjuvanting properties of the TNE
Summary
Invariant natural killer T (iNKT) cells are a subset of preactivated innate immune cells that possess markers of both NK and T cells and play a role in cancer immunity. The activation of iNKT cells requires T-cell receptor recognition of processed glycolipids presented on an MHC class I–like molecule, CD1d. Conventional dendritic cells (cDC) are specialized antigen-presenting cells (APC) that prime the adaptive immune system. Within this population of cells, CD8aþ cDCs are the dominant APC for cross-priming of antigen-specific T cells [1] and glycolipid presentation on CD1d for the activation of iNKT cells [2]. CDCs possess the appropriate machinery for capturing, processing, and presenting glycolipid antigens for the activation of iNKT cells [3]. Activation of iNKT cells provides helper signals via CD40–CD40L interactions [4] and chemokine signals [5] that augment DC maturation, production of IL12 and induction of innate immunity, including rapid activation of NK cells, and promotion of adaptive T-cell responses.
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