| Autor: |
Antoni Ribas, Siwen Hu-Lieskovan, Begoña Comin-Anduix, Beata Berent-Maoz, Catherine S. Grasso, Pau Mascaro, Christopher M. Lee, Agustin Vega-Crespo, Paige Krystofinski, Thomas Wohlwender, Gardenia Cheung-Lau, Cristina Puig-Saus, Angel Garcia-Diaz, Jesse M. Zaretsky, Giulia Parisi, Anusha Kalbasi, Katie M. Campbell, Jennifer Tsoi, Ameya S. Champhekar, Gabriel Abril-Rodriguez, Davis Y. Torrejon |
| Rok vydání: |
2023 |
| Popis: |
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 |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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