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; Lewis Zhichang Shi

doi:10.1038/s41467-022-32754-7

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, Lewis Zhichang Shi

Radiation Medicine

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

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 (IFNγR1^KO) impacts TILs. Here, we report that IFNγR1^KO melanomas have reduced infiltration and function of TILs. IFNγR1^KO 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 IFNγR1^KO 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.

Original language	English
Article number	5013
Journal	Nature Communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-32754-7
State	Published - Dec 2022

Bibliographical note

Funding Information:
We would like to acknowledge other members of Shi lab and the Department of Radiation Oncology at UAB for their constructive input. We are grateful for the Startup fund from the Department of Radiation Oncology and the O’Neal Invests pre-R01 Grant from the UAB-O’Neal Comprehensive Cancer Center granted to Shi lab. This study is also funded by National Institutes of Health grants (1R21CA230475-01A1 and 1R21CA259721-01A1), the V Foundation Scholar Award (V2018-023), a DoD-Congressionally Directed Medical Research Programs grant (ME210108), a Cancer Research Institute CLIP Grant (CRI4342), an American Cancer Society Institutional Research Grant (91-022-19), and National Institute of General Medical Sciences (1R35GM138212).

Funding Information:
We would like to acknowledge other members of Shi lab and the Department of Radiation Oncology at UAB for their constructive input. We are grateful for the Startup fund from the Department of Radiation Oncology and the O’Neal Invests pre-R01 Grant from the UAB-O’Neal Comprehensive Cancer Center granted to Shi lab. This study is also funded by National Institutes of Health grants (1R21CA230475-01A1 and 1R21CA259721-01A1), the V Foundation Scholar Award (V2018-023), a DoD-Congressionally Directed Medical Research Programs grant (ME210108), a Cancer Research Institute CLIP Grant (CRI4342), an American Cancer Society Institutional Research Grant (91-022-19), and National Institute of General Medical Sciences (1R35GM138212).

Publisher Copyright:
© 2022, The Author(s).

ASJC Scopus subject areas

Physics and Astronomy (all)
Chemistry (all)
Biochemistry, Genetics and Molecular Biology (all)

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10.1038/s41467-022-32754-7

Cite this

Shen, H., Huang, F., Zhang, X., Ojo, O. A., Li, Y., Trummell, H. Q., Anderson, J. C., Fiveash, J., Bredel, M., Yang, E. S., Willey, C. D., Chong, Z., Bonner, J. A., & Shi, L. Z. (2022). Selective suppression of melanoma lacking IFN-γ pathway by JAK inhibition depends on T cells and host TNF signaling. Nature Communications, 13(1), Article 5013. https://doi.org/10.1038/s41467-022-32754-7

@article{18b3099e915e415dbfb270ae9d5c1be5,

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

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.",

author = "Hongxing Shen and Fengyuan Huang and Xiangmin Zhang and Ojo, {Oluwagbemiga A.} and Yuebin Li and Trummell, {Hoa Quang} and Anderson, {Joshua C.} and John Fiveash and Markus Bredel and Yang, {Eddy S.} and Willey, {Christopher D.} and Zechen Chong and Bonner, {James A.} and Shi, {Lewis Zhichang}",

note = "Funding Information: We would like to acknowledge other members of Shi lab and the Department of Radiation Oncology at UAB for their constructive input. We are grateful for the Startup fund from the Department of Radiation Oncology and the O{\textquoteright}Neal Invests pre-R01 Grant from the UAB-O{\textquoteright}Neal Comprehensive Cancer Center granted to Shi lab. This study is also funded by National Institutes of Health grants (1R21CA230475-01A1 and 1R21CA259721-01A1), the V Foundation Scholar Award (V2018-023), a DoD-Congressionally Directed Medical Research Programs grant (ME210108), a Cancer Research Institute CLIP Grant (CRI4342), an American Cancer Society Institutional Research Grant (91-022-19), and National Institute of General Medical Sciences (1R35GM138212). Funding Information: We would like to acknowledge other members of Shi lab and the Department of Radiation Oncology at UAB for their constructive input. We are grateful for the Startup fund from the Department of Radiation Oncology and the O{\textquoteright}Neal Invests pre-R01 Grant from the UAB-O{\textquoteright}Neal Comprehensive Cancer Center granted to Shi lab. This study is also funded by National Institutes of Health grants (1R21CA230475-01A1 and 1R21CA259721-01A1), the V Foundation Scholar Award (V2018-023), a DoD-Congressionally Directed Medical Research Programs grant (ME210108), a Cancer Research Institute CLIP Grant (CRI4342), an American Cancer Society Institutional Research Grant (91-022-19), and National Institute of General Medical Sciences (1R35GM138212). Publisher Copyright: {\textcopyright} 2022, The Author(s).",

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doi = "10.1038/s41467-022-32754-7",

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T1 - Selective suppression of melanoma lacking IFN-γ pathway by JAK inhibition depends on T cells and host TNF signaling

AU - Shen, Hongxing

AU - Huang, Fengyuan

AU - Zhang, Xiangmin

AU - Ojo, Oluwagbemiga A.

AU - Li, Yuebin

AU - Trummell, Hoa Quang

AU - Anderson, Joshua C.

AU - Fiveash, John

AU - Bredel, Markus

AU - Yang, Eddy S.

AU - Willey, Christopher D.

AU - Chong, Zechen

AU - Bonner, James A.

AU - Shi, Lewis Zhichang

N1 - Funding Information: We would like to acknowledge other members of Shi lab and the Department of Radiation Oncology at UAB for their constructive input. We are grateful for the Startup fund from the Department of Radiation Oncology and the O’Neal Invests pre-R01 Grant from the UAB-O’Neal Comprehensive Cancer Center granted to Shi lab. This study is also funded by National Institutes of Health grants (1R21CA230475-01A1 and 1R21CA259721-01A1), the V Foundation Scholar Award (V2018-023), a DoD-Congressionally Directed Medical Research Programs grant (ME210108), a Cancer Research Institute CLIP Grant (CRI4342), an American Cancer Society Institutional Research Grant (91-022-19), and National Institute of General Medical Sciences (1R35GM138212). Funding Information: We would like to acknowledge other members of Shi lab and the Department of Radiation Oncology at UAB for their constructive input. We are grateful for the Startup fund from the Department of Radiation Oncology and the O’Neal Invests pre-R01 Grant from the UAB-O’Neal Comprehensive Cancer Center granted to Shi lab. This study is also funded by National Institutes of Health grants (1R21CA230475-01A1 and 1R21CA259721-01A1), the V Foundation Scholar Award (V2018-023), a DoD-Congressionally Directed Medical Research Programs grant (ME210108), a Cancer Research Institute CLIP Grant (CRI4342), an American Cancer Society Institutional Research Grant (91-022-19), and National Institute of General Medical Sciences (1R35GM138212). Publisher Copyright: © 2022, The Author(s).

PY - 2022/12

Y1 - 2022/12

N2 - 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.

AB - 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.

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ER -

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

Abstract

Bibliographical note

ASJC Scopus subject areas

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