Genome-wide discovery of cancer intrinsic immune resistance mechanisms in triple negative breast cancer

Patients with triple-negative breast cancer (TNBC) have poor survival rates and limited treatment options. In recent years, immune checkpoint blockade (ICB) therapy against the PD-1/L1 axis has proven efficacy human cancers.

However, only limited efficacy has been documented in TNBC, potentially due to the intrinsic resistance mechanisms in cancer cells.

In this proposal, we have identified the NEDD8 gene in human TNBC cancer cells as a key mechanism to confer resistance to the ICB therapy using genome-wide CRISPR screens.

We have successfully deleted the NEDD8 protein using CRISPR/Cas9 technology in a range of human and murine TNBC cell lines and will reveal the mechanistic insights of the pathway in vitro and in vivo.

Because NEDD8 is also expressed by immune cells, we will investigate its function in different immune cell subsets in humans and mice.

Finally, we aim to propose optimal targeting strategy for the neddylation pathway, either by refining the dose-scheduling of the existing compounds or invent new candidate drugs through drug discovery efforts.

Altogether, this proposal will elucidate the functional hierarchy and dominant immune resistant pathways in TNBC cancer cells which could lead to clinical benefits in this type of aggressive human cancer.