Selective suppression of melanoma lacking IFN-γ pathway by JAK inhibition depends on T cells and host TNF signaling

Hongxing Shen, Fengyuan Huang, Xiangmin Zhang, Oluwagbemiga A. Ojo, Yuebin Li, Hoa Quang Trummell, Joshua C. Anderson, John Fiveash, Markus Bredel, Eddy S. Yang, Christopher D. Willey, Zechen Chong (), James A. Bonner () and Lewis Zhichang Shi ()
Additional contact information
Hongxing Shen: University of Alabama at Birmingham (UAB-SOM)
Fengyuan Huang: Department of Genetics and Informatics Institute
Xiangmin Zhang: Wayne State University
Oluwagbemiga A. Ojo: University of Alabama at Birmingham (UAB-SOM)
Yuebin Li: University of Alabama at Birmingham (UAB-SOM)
Hoa Quang Trummell: University of Alabama at Birmingham (UAB-SOM)
Joshua C. Anderson: University of Alabama at Birmingham (UAB-SOM)
John Fiveash: University of Alabama at Birmingham (UAB-SOM)
Markus Bredel: University of Alabama at Birmingham (UAB-SOM)
Eddy S. Yang: University of Alabama at Birmingham (UAB-SOM)
Christopher D. Willey: University of Alabama at Birmingham (UAB-SOM)
Zechen Chong: Department of Genetics and Informatics Institute
James A. Bonner: University of Alabama at Birmingham (UAB-SOM)
Lewis Zhichang Shi: University of Alabama at Birmingham (UAB-SOM)

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract Therapeutic resistance to immune checkpoint blockers (ICBs) in melanoma patients is a pressing issue, of which tumor loss of IFN-γ signaling genes is a major underlying mechanism. However, strategies of overcoming this resistance mechanism have been largely elusive. Moreover, given the indispensable role of tumor-infiltrating T cells (TILs) in ICBs, little is known about how tumor-intrinsic loss of IFN-γ signaling (IFNγR1KO) impacts TILs. Here, we report that IFNγR1KO melanomas have reduced infiltration and function of TILs. IFNγR1KO melanomas harbor a network of constitutively active protein tyrosine kinases centered on activated JAK1/2. Mechanistically, JAK1/2 activation is mediated by augmented mTOR. Importantly, JAK1/2 inhibition with Ruxolitinib selectively suppresses the growth of IFNγR1KO but not scrambled control melanomas, depending on T cells and host TNF. Together, our results reveal an important role of tumor-intrinsic IFN-γ signaling in shaping TILs and manifest a targeted therapy to bypass ICB resistance of melanomas defective of IFN-γ signaling.

Date: 2022
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DOI: 10.1038/s41467-022-32754-7

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