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Biphasic function of TLR3 adjuvant on tumor and spleen dendritic cells promotes tumor T cell infiltration and regression in a vaccine therapy.

ABSTRACT: Successful cancer immunotherapy necessitates T cell proliferation and infiltration into tumor without exhaustion, a process closely links optimal maturation of dendritic cells (DC), and adjuvant promotes this process as an essential prerequisite. Poly(I:C) has contributed to adjuvant immunotherapy that evokes an antitumor response through the Toll-loke receptor 3 (TLR3)/TICAM-1 pathway in DC. However, the mechanism whereby Poly(I:C) acts on DC for T cell proliferation and migration remains undetermined. Subcutaneous injection of Poly(I:C) regressed implant tumors (WT1-C1498 or OVA-EG7) in C57BL/6 mice, which coincided with tumor-infiltration of CD8(+) T cells. Epitope-specific cytotoxic T lymphocytes (CTLs) were increased in spleen by challenge with Poly(I:C)+Db126 WT-1 peptide but not Poly(I:C) alone, suggesting the need of an exogenous Ag density for cross-priming. In tumor, CXCR3 ligands were upregulated by Poly(I:C), which facilitated recruitment of CTL to the tumor. Thus, Poly(I:C) acts on splenic CD8α(+) DC to cross-prime T cells and on intratumor cells to attract CTLs. Besides CD8(+) T cell cross-priming, T cell recruitment into tumor was significantly dampened in Batf3 (-/-) mice, reflecting the importance of tumor Batf3-dependent DC rather than macrophages in T cell recruitment. Poly(I:C)-induced XCR1(hi) CD8α(+) DC with high TLR3 levels were markedly decreased in Batf3 (-/-) mice, which hampered the production of IL-12 and IL-12-mediated CD4(+)/CD8(+) T cell proliferation. Subcutaneous administration of Poly(I:C) and adoptive transfer of wild-type CD8α(+) DC largely recovered antitumor response in those Batf3 (-/-) mice. Collectively, Poly(I:C) tunes up proper maturation of CD8α(+) DC to establish TLR3-mediated IL-12 function and cross-presentation in spleen and lymphocyte-attractive antitumor microenvironment in tumor.

SUBMITTER: Azuma M

PROVIDER: S-EPMC5007976 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:MF59 is an oil-in-water emulsion adjuvant approved for human influenza vaccination in European Union. The mode of action of MF59 is not fully elucidated yet, but results from several years of investigation indicate that MF59 establishes an immunocompetent environment at injection site which promotes recruitment of immune cells, including antigen presenting cells (APCs), that are facilitated to engulf antigen and transport it to draining lymph node (dLN) where the antigen is accumulated. In vitro studies showed that MF59 promotes the differentiation of monocytes to dendritic cells (Mo-DCs). Since after immunization with MF59, monocytes are rapidly recruited both at the injection site and in dLN and appear to have a morphological change toward a DC-like phenotype, we asked whether MF59 could play a role in inducing differentiation of Mo-DC in vivo. To address this question we immunized mice with the auto-fluorescent protein Phycoerythrin (PE) as model antigen, in presence or absence of MF59. We measured the APC phenotype and their antigen uptake within dLNs, the antigen distribution within the dLN compartments and the humoral response to PE. In addition, using Ovalbumin as model antigen, we measured the capacity of dLN APCs to induce antigen-specific CD4 T cell proliferation. Here, we show, for the first time, that MF59 promotes differentiation of Mo-DCs within dLNs from intranodal recruited monocytes and we suggest that this differentiation could take place in the medullary compartment of the LN. In addition we show that the Mo-DC subset represents the major source of antigen-loaded and activated APCs within the dLN when immunizing with MF59. Interestingly, this finding correlates with the enhanced triggering of antigen-specific CD4 T cell response induced by LN APCs. This study therefore demonstrates that MF59 is able to promote an immunocompetent environment also directly within the dLN, offering a novel insight on the mechanism of action of vaccine adjuvants based on emulsions.

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Biphasic function of TLR3 adjuvant on tumor and spleen dendritic cells promotes tumor T cell infiltration and regression in a vaccine therapy.

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