Targeting NKT cells and PD-L1 pathway results in augmented anti-tumor responses in a melanoma model

Abstract

Invariant or Type 1 NKT cells (iNKT cells) are a unique population of lymphocytes that share characteristics of T cells and natural killer (NK) cells. Various studies have shown that positive costimulatory pathways such as the CD28 and CD40 pathways can influence the expansion and cytokine production by iNKT cells. However, little is understood about the regulation of iNKT cells by negative costimulatory pathways. Here, we show that in vivo activation with α-GalCer results in increased cytokine production and expansion of iNKT cells in the absence of programmed cell death ligand-1 (PD-L1, B7-H1, and CD274). To study whether PD-L1 deficiency on NKT cells would enhance antigen-specific T-cell responses, we utilized CD8+ OT-1 OVA transgenic T cells. α-GalCer enhanced the expansion and cytokine production of OT-1 CD8+ cells after adoptive transfer into wild-type recipients. However, this expansion was significantly enhanced when OT-1 CD8+ T cells were adoptively transferred into PD-L1−/− recipients. To extend these results to a tumor model, we used the B16 melanoma system. PD-L1−/− mice given dendritic cells loaded with antigen and α-GalCer had a significant reduction in tumor growth and this was associated with increased trafficking of antigen-presenting cells and CD8+ T cells to the tumors. These data demonstrate that abrogating PDL1:PD-1 interactions during the activation of iNKT cells amplifies an anti-tumor response when coupled with DC vaccination.

Broadening the Message: A Nanovaccine Co-loaded with Messenger RNA and α-GalCer Induces Antitumor Immunity through Conventional and Natural Killer T Cells

“…While literature contains conflicting data about iNKT anergy, multiple studies reported that the PD-1/PD-L1 checkpoint pathway plays a critical role in regulation of iNKT cell activity. 42,57,61 When investigating the involvement of this checkpoint axis in the present study, we confirmed the up-regulation of PD-1 in activated NKT cells, as well as its ligand PD-L1 in APCs in the systemic organs ( Figure 5 and Figure S9). We could also detect a pronounced PD-L1 expression in tumors of nanoparticle-treated animals.…”

Immunological in vivo effects of B7-H1 deficiency

“…Interestingly, the B7-CD28 co-stimulatory pathway can modulate development of NKT cells [57,58] and PD-1/PD-L1 interaction is essential for the induction and maintenance of iNKT cell anergy. PD-1/PD-L blockade prevents anergy induction and enhances the anti-tumor activities of glycolipid-activated invariant NKT cells in the melanoma model [59]. We detected an increase in PD-1 expression on NK and NKT cells; however, it did not lead to augmented expansion of NKT cells in healthy B7-H1KO mice.…”

Activation of NKT Cells in an Anti-PD-1–Resistant Tumor Model Enhances Antitumor Immunity by Reinvigorating Exhausted CD8 T Cells

“…Administration of aGC is known to induce iNKT cell anergy by triggering the upregulation of PD-1 on iNKT cells (48). We and others have previously demonstrated that blocking the PD-1/PD-L1 interaction can prevent anergy induction in iNKT cells and enhance the antitumor effects of iNKT cells (48)(49)(50). In advanced tumors, NK cells also express Tim-3 and PD-1 and become functionally exhausted (31).…”