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 journalArticle

2 Citations (Scopus)

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)
JournalOncoImmunology
DOIs
StateAccepted/In press - Mar 5 2018

Fingerprint

Immunotherapy
Melanoma
Cell Death
Ligands
Programmed Cell Death 1 Receptor
Neoplasms
Cytostatic Agents
Interferon-gamma
Therapeutics
Antigens
Survival

Keywords

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

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Oncology

Cite this

Luo, N., Formisano, L., Gonzalez-Ericsson, P. I., Sanchez, V., Dean, P. T., Opalenik, S. R., ... Balko, J. M. (Accepted/In press). Melanoma response to anti-PD-L1 immunotherapy requires JAK1 signaling, but not JAK2. OncoImmunology. https://doi.org/10.1080/2162402X.2018.1438106

Melanoma response to anti-PD-L1 immunotherapy requires JAK1 signaling, but not JAK2. / Luo, Na; Formisano, Luigi; Gonzalez-Ericsson, Paula I.; Sanchez, Violeta; Dean, Phillip T.; Opalenik, Susan R.; Sanders, Melinda E.; Cook, Rebecca S.; Arteaga, Carlos L.; Johnson, Douglas B.; Balko, Justin M.

In: OncoImmunology, 05.03.2018.

Research output: Contribution to journalArticle

Luo, N, Formisano, L, Gonzalez-Ericsson, PI, Sanchez, V, Dean, PT, Opalenik, SR, Sanders, ME, Cook, RS, Arteaga, CL, Johnson, DB & Balko, JM 2018, 'Melanoma response to anti-PD-L1 immunotherapy requires JAK1 signaling, but not JAK2', OncoImmunology. https://doi.org/10.1080/2162402X.2018.1438106
Luo N, Formisano L, Gonzalez-Ericsson PI, Sanchez V, Dean PT, Opalenik SR et al. Melanoma response to anti-PD-L1 immunotherapy requires JAK1 signaling, but not JAK2. OncoImmunology. 2018 Mar 5. https://doi.org/10.1080/2162402X.2018.1438106
Luo, Na ; Formisano, Luigi ; Gonzalez-Ericsson, Paula I. ; Sanchez, Violeta ; Dean, Phillip T. ; Opalenik, Susan R. ; Sanders, Melinda E. ; Cook, Rebecca S. ; Arteaga, Carlos L. ; Johnson, Douglas B. ; Balko, Justin M. / Melanoma response to anti-PD-L1 immunotherapy requires JAK1 signaling, but not JAK2. In: OncoImmunology. 2018.
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