Checkpoint receptors expressed by dendritic cells- do they play a role in immunotherapies?
Worldwide Cancer Research
Monash University
The preliminary data of this proposal indicate that PD-1 and other checkpoint inhibitors are upregulated on DC upon activation both in vitro and in vivo. The panel of immune checkpoint proteins expressed by DC is governed by their specific subset. Moreover, human DC subsets show similar upregulation of PD-1 upon activation. Our examination of DC of PD-1 knockout mice has revealed that this protein is involved in the regulation of interferon-lambda production by DC subsets and in the T cell stimulation capacity of DC. This is particularly striking in the cross-presenting CD8+ DC, also known as conventional (c) DC1. Moreover, blocking of PD-1 signalling on human DC using small molecule inhibitors of PD-1 also leads to enhanced IFN-lambda producing capacity of cDC1. This project aims to decipher exactly how PD-1 signalling in DC affects transcriptional regulation and overall function in these cells. We will determine the PD-1 expression on DC in mouse models of induced melanoma. We will determine how PD-1 expression on DC determines outcome of melanoma growth pre and post treating with PD-1 blocking agents. Our work will reveal the functional significance of PD-1 expression by DC, revealing for the first time how these cells must be taken into account when designing immune checkpoint immunotherapies.
2.1 Biological and endogenous factors