Send to

Choose Destination
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

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


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.


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

Supplemental Content

Full text links

Icon for Taylor & Francis Icon for PubMed Central
Loading ...
Support Center