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

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

20 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

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

Funding

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). 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).

Funders	Funder number
Department of Radiation Oncology
UAB-O’Neal Comprehensive Cancer Center
National Institutes of Health (NIH)	1R21CA230475-01A1
National Institutes of Health (NIH)
American Cancer Society-Michigan Cancer Research Fund	91-022-19
American Cancer Society-Michigan Cancer Research Fund
National Childhood Cancer Registry – National Cancer Institute	R21CA259721
National Childhood Cancer Registry – National Cancer Institute
National Institute of General Medical Sciences DP2GM119177 Sophie Dumont National Institute of General Medical Sciences	1R35GM138212
National Institute of General Medical Sciences DP2GM119177 Sophie Dumont National Institute of General Medical Sciences
Congressionally Directed Medical Research Programs	ME210108
Congressionally Directed Medical Research Programs
Children's Cancer Research Institute, Vienna	CRI4342
Children's Cancer Research Institute, Vienna
V Foundation for Cancer Research	V2018-023
V Foundation for Cancer Research
University of Alabama, Birmingham

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General
General Physics and Astronomy

Access to Document

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 = "Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

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

language = "English",

volume = "13",

number = "1",

}

TY - JOUR

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

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.

UR - http://www.scopus.com/inward/record.url?scp=85136653434&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85136653434&partnerID=8YFLogxK

U2 - 10.1038/s41467-022-32754-7

DO - 10.1038/s41467-022-32754-7

M3 - Article

C2 - 36008408

AN - SCOPUS:85136653434

SN - 2041-1723

VL - 13

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 5013

ER -

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

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this