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Dual TLR9 and PD-L1 targeting unleashes dendritic cells to induce durable anti-tumor immunity (Zippelius Lab)
This study reports a PD-L1-targeting antisense oligonucleotide with TLR9 agonistic capacity that stimulates intratumoral DC3s while modulating their PD-L1 expression, thereby inducing long-lasting tumor control in multiple mouse tumor models. It also provides human DC data to apply these findings to the treatment of human cancers.
Although immune checkpoint inhibitors (ICIs) have been a breakthrough in clinical oncology, these therapies often fail to produce durable responses in a significant proportion of patients. This lack of long-term efficacy may be attributed to a poor pre-existing network that connects innate and adaptive immunity. In a recent study led by Professor Alfred Zippelius, researchers present an antisense oligonucleotide (ASO)-based strategy targeting both TLR9 and PD-L1 (IM-T9P1-ASO), with the aim of overcoming resistance to anti-PD-L1 monoclonal therapy.
They show that, in contrast to PD-L1 antibody therapy, IM-T9P1-ASO therapy induces durable anti-tumor responses in multiple mouse cancer models. Mechanistically, IM-T9P1-ASO activates a state of tumor-associated dendritic cells, called DC3s, which possess potent anti-tumor potential but express the PD-L1 checkpoint. IM-T9P1-ASO not only induces the expansion of DC3s by binding to TLR9, but also downregulates PD-L1, thereby fully unleashing their anti-tumor functions and resulting in T-cell-mediated tumor rejection. The team also reveal the critical roles of IL-12, an anti-tumor cytokine produced by DC3s, and Batf3, a transcription factor required for DC development, in the anti-tumor effectiveness of IM-T9P1-ASO. As in mice, human intratumoral DC3s are the cells with the highest PD-L1 expression and express TLRs.
Their findings demonstrate that ASO-mediated dual targeting of TLR9 and PD-L1 enhances anti-tumor responses and leads to durable therapeutic efficacy by acting on multiple arms of anti-tumor immunity,. Overall, this study provides valuable mechanistic insights for the design of future therapies aimed at stimulating intratumoral DCs through TLRs while simultaneously controlling their PD-L1 expression, achieving better control over the growth and progression of solid tumors.