Xue et al. showed that treating tumor-bearing mice with anti-PD-1 and a near infrared (NIR) convertible dye-linked Ab specific for a tumor antigen allowed the outgrowth of antigenic-variant tumor cells resistant to anti-PD-1. Resistance was subverted when hosts received tumor-focused NIR irradiation after IV injection of a dye-linked anti-CD73 Ab. This regimen promoted CD73- CTL activity and death of CD73+ suppressor cells and of NIR-irradiated and distal non-irradiated CD73+and- tumor cells, and induced regression of advanced tumors when combined with ICB. The regimen also sensitized PDAC patient-derived spheroids to anti-PD-1.
Contributed by Paula Hochman
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.
Author Info: (1) Comprehensive Cancer Center, Wake Forest Baptist Health, Winston-Salem, NC, USA. Department of Microbiology and Immunology, Wake Forest School of Medicine, Winston-Salem, NC, U
Author Info: (1) Comprehensive Cancer Center, Wake Forest Baptist Health, Winston-Salem, NC, USA. Department of Microbiology and Immunology, Wake Forest School of Medicine, Winston-Salem, NC, USA. (2) Comprehensive Cancer Center, Wake Forest Baptist Health, Winston-Salem, NC, USA. Department of Microbiology and Immunology, Wake Forest School of Medicine, Winston-Salem, NC, USA. (3) Comprehensive Cancer Center, Wake Forest Baptist Health, Winston-Salem, NC, USA. Department of Microbiology and Immunology, Wake Forest School of Medicine, Winston-Salem, NC, USA. (4) Comprehensive Cancer Center, Wake Forest Baptist Health, Winston-Salem, NC, USA. Department of Microbiology and Immunology, Wake Forest School of Medicine, Winston-Salem, NC, USA. (5) Comprehensive Cancer Center, Wake Forest Baptist Health, Winston-Salem, NC, USA. Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC, USA. (6) Department of Mathematics and Statistics, St. Cloud State University, Saint Cloud, MN, USA. (7) Comprehensive Cancer Center, Wake Forest Baptist Health, Winston-Salem, NC, USA. Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC, USA. (8) Comprehensive Cancer Center, Wake Forest Baptist Health, Winston-Salem, NC, USA. Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC, USA. (9) Comprehensive Cancer Center, Wake Forest Baptist Health, Winston-Salem, NC, USA. yolu@wakehealth.edu. Department of Microbiology and Immunology, Wake Forest School of Medicine, Winston-Salem, NC, USA. yolu@wakehealth.edu.
