Abstract
Tumors that lack pre-existing immune infiltration respond poorly to T cell checkpoint blockade immunotherapy. These cancers often surround themselves with high densities of suppressive myeloid stroma while excluding immunostimulatory dendritic cells. Tumor-resident myeloid cells and selected lymphocyte populations retain expression of Toll-like Receptors (TLR) that sense common features of pathogens and activate innate immunity in response. We explored whether agonists of TLR9 could augment innate immunity to promote tumor regression alone or in combination with T cell checkpoint blockade. In the setting of the immunogenic B16-Ova (Ovalbumin) expressing melanoma model, local injection of the CpG oligonucleotide TLR9 agonist ODN1826 combined with systemic CTLA-4 blockade cured 45% of mice of both their treated and an untreated tumor on the opposite flank demonstrating the synergistic potential of this combination. Next, in the non-immunogenic B16-F10 melanoma model, we showed that only intra-tumoral, but not systemic TLR9 activation augments the therapeutic potential of checkpoint blockade. In this setting, intra-tumoral TLR9 activation cooperated equally with either CTLA-4 or PD-1 blockade co-administered locally or given systemically; however, the uninjected tumor rarely regressed. Anti-CTLA-4 combinations were associated with improved intra-tumoral CD8 to regulatory T cell ratios, while anti-PD-1 combinations elicited improved ratios of CD8 T cells relative to suppressive myeloid stroma. Using both a TLR9 agonist (MGN1703) and a CTLA-4 antibody (9D9-IgG2a) of increased potency cured 50% of bi-lateral B16-F10 melanoma. These findings suggest that intra-tumoral TLR9 agonists can improve sensitivity of poorly immunogenic tumors to T cell checkpoint blockade, and that newer, higher potency TLR agonists and checkpoint antibodies can raise the therapeutic ceiling for this combination therapy.
Highlights
Tumors actively condition their microenvironments to foster recruitment of suppressive myeloid stroma and dampen accumulation of potentially immunostimulatory antigen-presenting cells such as dendritic cells
As innate agonists of both Toll-like receptors (TLR) and the Stimulator of Interferon Genes pathways are being administered to patients both intratumorally as well as systemically, we investigated the impact of route of delivery on the efficacy of ODN1826 with or without anti-Cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) or anti-PD-1 on the progression of bi-laterally implanted B16-F10 parental melanoma
B16-ova melanoma We sought to test whether activation of Toll-like receptor 9 (TLR9) through intra-tumoral injection in the B16-Ova melanoma model could potentiate systemic, sterilizing anti-tumor immunity in conjunction with blockade of the T cell immune checkpoint receptor CTLA-4
Summary
Tumors actively condition their microenvironments to foster recruitment of suppressive myeloid stroma and dampen accumulation of potentially immunostimulatory antigen-presenting cells such as dendritic cells. The predominant M2 macrophage and myeloid-derived suppressor cell (MDSC) composition of the myeloid stroma effectively shields the tumor from any adaptive immune effectors which do become mobilized In this setting, blockade of T cell immune checkpoint receptors is often insufficient to mediate any significant regression of cancer. Provision of toll-like receptor ligands has the potential to reactivate tumor stroma, myeloid cells and B cells, increasing both tumor antigen crosspresentation and pro-inflammatory cytokine production [1]. These direct effects on innate immune activation, in turn, foster enhanced activation of adaptive immune effectors (i.e. T and NK cells) increasing both baseline
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