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 IFNγR1KOmelanomas have reduced infiltration and function of TILs. IFNγR1KOmelanomas 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 IFNγR1KObut 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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Aug 25, 2022
- Source ID
- 10.1038/s41467-022-32754-7
Entities
People
- Christopher D. Willey
- Eddy S Yang
- Fengyuan Huang
- Hoa Quang Trummell
- Hongxing Shen
- James A. Bonner
- John Fiveash
- Joshua C. Anderson
- Lewis Zhichang Shi
- Markus Bredel
- Oluwagbemiga A. Ojo
- Xiangmin Zhang
- Yuebin Li
- Zechen Chong
Organizations
- American Cancer Society
- Cancer Research Institute
- Comprehensive Cancer Center, University of Alabama at Birmingham
- National Cancer Institute
- National Institute of General Medical Sciences
- United States Department of Defense
- United States Department of Health and Human Services