Abstract
Targeting TLR3 through formulations of polyI:C is widely studied as an adjuvant in cancer immunotherapy. The efficacy of such targeting has been shown to increase in combination with anti-PD-L1 treatment. Nevertheless, the mechanistic details of the effect of polyI:C on DC maturation and the impact on T-DC interactions upon PD-L1 blockade is largely unknown. Here we found that although DC treatment with polyI:C induced a potent inflammatory response including the production of type I interferon, polyI:C treatment of DCs impaired activation of peptide specific CD8+ T cells mainly due to PD-L1. Interestingly, we found that PD-L1 trafficking to the cell surface is regulated in two waves in polyI:C-treated DCs. One induced upon overnight treatment and a second more rapid one, specific to polyI:C treatment, was induced upon CD40 signaling leading to a further increase in surface PD-L1 in DCs. The polyI:C-induced cell surface PD-L1 reduced the times of contact between DCs and T cells, potentially accounting for limited T cell activation. Our results reveal a novel CD40-dependent regulation of PD-L1 trafficking induced upon TLR3 signaling that dictates its inhibitory activity. These results provide a mechanistic framework to understand the efficacy of anti-PD-L1 cancer immunotherapy combined with TLR agonists.
Highlights
The pathogen recognition receptor, Toll-like receptor 3 [1] recognizes double-stranded RNA of certain viruses to induce a potent innate immune response crucial for pathogen control [2,3,4,5]
The unexpected observation that T cell proliferation induced by polyI:C, but not LPS-treated DCs, was susceptible to PD-L1 blockade led us to question whether PD-L1 itself was regulated differently between the two DC populations
Celastrol treatment reduced basal CD86 expression but there was no effect on CD86 expression upon CD40L treatment (Fig 4C, right panel). These results indicate that PD-L1 trafficking to the cell surface upon CD40 signalling is selectively modulated in polyI:C pre-treated DCs in an NF-kB dependent manner
Summary
The pathogen recognition receptor, Toll-like receptor 3 [1] recognizes double-stranded RNA (dsRNA) of certain viruses to induce a potent innate immune response crucial for pathogen control [2,3,4,5]. Several human tumours express high levels of TLR3 [6] that is being targeted in immunotherapeutic protocols to initiate both innate and adaptive immune responses. PolyI:C, a synthetic dsRNA mimetic and its formulations have shown promising results when administered alone or in combination with other ligands as adjuvants in immunotherapy in both human cancers and in murine tumour models [7, 8]. Two main characteristics of TLR3 signalling make it an ideal target in immunotherapy: i. TLR3 is preferentially expressed in cross-presenting DCs and promotes cross-priming of endogenous antigens thereby.
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