Melanoma response to anti-PD-L1 immunotherapy requires JAK1 signaling, but not JAK2

Na Luo, Luigi Formisano, Paula I. Gonzalez-Ericsson, Violeta Sanchez, Phillip T. Dean, Susan R. Opalenik, Melinda E. Sanders, Rebecca S. Cook, Carlos L. Arteaga, Douglas B. Johnson, Justin M. Balko

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Immunotherapies targeting programmed cell death protein 1 (PD-1) or its ligand, programmed cell death ligand 1 (PD-L1), dramatically improve the survival of melanoma patients. However, only ∼40% of treated patients demonstrate a clinical response to single-agent anti-PD-1 therapy. An intact tumor response to type-II interferon (i.e. IFN-γ) correlates with response to anti-PD-1, and patients with de novo or acquired resistance may harbor loss-of-function alterations in the JAK/STAT pathway, which lies downstream of the interferon gamma receptor (IFNGR1/2). In this study, we dissected the specific roles of individual JAK/STAT pathway members on the IFN-γ response, and identified JAK1 as the primary mediator of JAK/STAT signaling associated with IFN-γ-induced expression of antigen-presenting molecules MHC-I and MHC-II, as well as PD-L1 and the cytostatic response to IFN-γ. In contrast to the crucial role of JAK1, JAK2 was largely dispensable in mediating most IFN-γ effects. In a mouse melanoma model, inhibition of JAK1/2 in combination with anti-PD-L1 therapy partially blocked anti-tumor immunologic responses, while selective JAK2 inhibition appeared to augment therapy. Amplification of JAK/STAT signaling in tumor cells through genetic inhibition of the negative regulator PTPN2 potentiated IFN-γ response in vitro and in vivo, and may be a target to enhance immunotherapy efficacy.

Original languageEnglish (US)
Article numbere1438106
JournalOncoImmunology
Volume7
Issue number6
DOIs
StatePublished - Jun 3 2018

Keywords

  • IFN-γ
  • JAK/STAT
  • PTPN2
  • checkpoint immunotherapy

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Oncology

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