Combined targeting of PD-L1 and NFκB pathways to reverse T-cell exhaustion and restore anti-tumour immunity in breast cancer

The majority of deaths from breast cancer following conventional therapies are a result of metastases. Programmed death 1 ligand (PD-L1), a negative regulator of the immune system, is highly expressed in triple negative breast tumours and cell lines, and its expression is associated with suppressed anti-tumour immunity. Therapeutic antibodies directed at PD-L1 have shown promise for the treatment of cancer, however only a small proportion of patients respond to these agents. NFκB pathway is implicated in tumour growth, metastasis and T-cell exhaustion in breast cancer. We have identified a family of novel class of small-molecule NFκB inhibitors that exhibited anti-inflammatory, anti-tumour, and anti-metastatic properties in preclinical models of inflammation and cancer. Our recent unpublished data in human breast cancer cells showed that the lead compound reduced cell growth, migration, and invasion in vitro and when combined with PD-L1 inhibitor 1, it accelerated cancer cell death.

The main aims of this application are two fold; (a) test the effects of combined pharmacological inhibition and genetic modulation of NFKB and PD-L1 on tumour growth and metastasis in humanized and syngeneic mouse models of breast cancer, and (b) Determine the mechanism(s) by which NFKB regulates PD-L1-driven breast cancer - T-cell interactions. If successful, the findings of this research will have translational potential in demonstrating that NFκB inhibitors - in combination therapy with PD-L1 inhibitors - may be of value in restoring the cytotoxic function of tumour antigen-specific T cells, thereby yielding durable response in metastatic breast cancer. This addresses a huge unmet clinical need, as metastasis, poor response to immunotherapy and acquired resistance to chemotherapeutic agents are major clinical problems.