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

Overcoming Genetically Based Resistance Mechanisms to PD-1 Blockade

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  • Media type: E-Article
  • Title: Overcoming Genetically Based Resistance Mechanisms to PD-1 Blockade
  • Contributor: Torrejon, Davis Y.; Abril-Rodriguez, Gabriel; Champhekar, Ameya S.; Tsoi, Jennifer; Campbell, Katie M.; Kalbasi, Anusha; Parisi, Giulia; Zaretsky, Jesse M.; Garcia-Diaz, Angel; Puig-Saus, Cristina; Cheung-Lau, Gardenia; Wohlwender, Thomas; Krystofinski, Paige; Vega-Crespo, Agustin; Lee, Christopher M.; Mascaro, Pau; Grasso, Catherine S.; Berent-Maoz, Beata; Comin-Anduix, Begoña; Hu-Lieskovan, Siwen; Ribas, Antoni
  • imprint: American Association for Cancer Research (AACR), 2020
  • Published in: Cancer Discovery
  • Language: English
  • DOI: 10.1158/2159-8290.cd-19-1409
  • ISSN: 2159-8274; 2159-8290
  • Origination:
  • Footnote:
  • Description: <jats:title>Abstract</jats:title> <jats:sec> <jats:title /> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Significance:</jats:title> <jats:p>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.</jats:p> <jats:p>This article is highlighted in the In This Issue feature, p. 1079</jats:p> </jats:sec>
  • Access State: Open Access