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

Gang Xue, Ziyu Wang, Ningbo Zheng, Jing Fang, Chengqiong Mao, Xiaoyin Li, Guangxu Jin, Xin Ming, Yong Lu

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1306-1319
Number of pages14
JournalNature Biomedical Engineering
Volume5
Issue number11
DOIs
StatePublished - Nov 2021

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Medicine (miscellaneous)
  • Biomedical Engineering
  • Computer Science Applications

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