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Oncoimmunology. 2018 Mar 6;7(6):e1438106. doi: 10.1080/2162402X.2018.1438106. eCollection 2018.

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

Author information

1
Department of Anatomy and Histology, School of Medicine, Nankai University, Tianjin, China.
2
Departments of Medicine, Vanderbilt University Medical Center, Nashville TN, USA.
3
Breast Cancer Research Program, Vanderbilt University Medical Center, Nashville TN, USA.
4
Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville TN, USA.
5
Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville TN, USA.
6
Cancer Biology Program, Vanderbilt University Medical Center, Nashville TN, USA.
7
Department of Biomedical Engineering, Vanderbilt University Medical Center, Nashville TN.

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.

KEYWORDS:

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

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