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

The concurrent depletion of tumour cells and immunosuppressive cells via a monoclonal antibody targeting a common surface marker prevents tumours from acquiring resistance to therapies involving immune checkpoint blockade. Antigen release resulting from the death of tumour cells induced by chemotherapies and targeted therapies can augment the antitumour 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 cell via a monoclonal antibody binding the enzyme CD73, which we identified as highly expressed on tumour cells and on regulatory T cells, myeloid-derived suppressor cells and tumour-associated macrophages, but 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 prevented 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.

Automated summary

Targeting tumor cells can promote resistance to immune checkpoint blockade therapy, but this resistance can be overcome by depleting tumor cells and immunosuppressive cells simultaneously using a monoclonal antibody binding CD73 enzyme. This approach prevents tumors from acquiring resistance to immune checkpoint blockade and leads to the eradication of advanced tumors.