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Cancer Discov ; 10(8): 1140-1157, 2020 08.
Article in English | MEDLINE | ID: mdl-32467343

ABSTRACT

Mechanism-based strategies to overcome resistance to PD-1 blockade therapy are urgently needed. We developed genetic acquired resistant models of JAK1, JAK2, and B2M loss-of-function mutations by gene knockout in human and murine cell lines. Human melanoma cell lines with JAK1/2 knockout became insensitive to IFN-induced antitumor effects, while B2M knockout was no longer recognized by antigen-specific T cells and hence was resistant to cytotoxicity. All of these mutations led to resistance to anti-PD-1 therapy in vivo. JAK1/2-knockout resistance could be overcome with the activation of innate and adaptive immunity by intratumoral Toll-like receptor 9 agonist administration together with anti-PD-1, mediated by natural killer (NK) and CD8 T cells. B2M-knockout resistance could be overcome by NK-cell and CD4 T-cell activation using the CD122 preferential IL2 agonist bempegaldesleukin. Therefore, mechanistically designed combination therapies can overcome genetic resistance to PD-1 blockade therapy. SIGNIFICANCE: The activation of IFN signaling through pattern recognition receptors and the stimulation of NK cells overcome genetic mechanisms of resistance to PD-1 blockade therapy mediated through deficient IFN receptor and antigen presentation pathways. These approaches are being tested in the clinic to improve the antitumor activity of PD-1 blockade therapy.This article is highlighted in the In This Issue feature, p. 1079.


Subject(s)
Drug Resistance, Neoplasm/genetics , Janus Kinase 1/genetics , Janus Kinase 2/genetics , Programmed Cell Death 1 Receptor/antagonists & inhibitors , beta 2-Microglobulin/genetics , Animals , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Interferons/pharmacology , Interleukin-2/analogs & derivatives , Interleukin-2/immunology , Interleukin-2/pharmacology , Interleukin-2/therapeutic use , Killer Cells, Natural/immunology , Loss of Function Mutation , Mice, Inbred C57BL , Neoplasms/drug therapy , Neoplasms/genetics , Neoplasms/immunology , Polyethylene Glycols/pharmacology , Polyethylene Glycols/therapeutic use , Toll-Like Receptor 9/immunology
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