Elimination of acquired resistance to PD-1 blockade via the concurrent depletion of tumour cells and immunosuppressive cells

Antigen release resulting from the death of tumour cells induced by chemotherapies and targeted therapies can augment the antitumor responses induced by immune checkpoint blockade (ICB). However, tumours responding to ICB therapies often become resistant to them. Here, we show that the specific targeting of tumour cells promotes the growth of tumour-cell variants that are resistant to ICB, and that the acquired resistance can be overcome via the concurrent depletion of tumour cells and of major types of immunosuppressive cells via a monoclonal antibody binding the enzyme CD73 (which we identified is highly expressed on tumour cells and on regulatory T cells, myeloid-derived suppressor cells and tumour-associated macrophages, yet not on cytolytic T lymphocytes, natural killer cells and dendritic cells). In mice with murine tumours, the systemic administration of anti-PD1 antibodies and anti-CD73 antibodies conjugated to a near-infrared dye subverted near-infrared-irradiated tumours from acquiring resistance to ICB and resulted in the eradication of advanced tumours. The elimination of immunosuppressive cells may overcome acquired resistance to ICB across a range of tumour types and combination therapies.