IFN-γ in ovarian tumor microenvironment upregulates HLA-E expression and predicts a poor prognosis

  • J Ovarian Res. 2023 Nov 25;16(1):229. doi: 10.1186/s13048-023-01286-z.
Hui Zheng  #  1 ,  Xiaolin Guan  #  2  3 ,  Xin Meng  2 ,  Ying Tong  1 ,  Yanchun Wang  1 ,  Suhong Xie  1 ,  Lin Guo  4  5 ,  Renquan Lu  6  7
Affiliations
  • 1. Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
  • 2. Department of Oncology, Shanghai Medical College of Fudan University, Shanghai, 200032, China.
  • 3. Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai, 200032, China.
  • 4. Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai, 200032, China. [email protected].
  • 5. Department of Oncology, Shanghai Medical College of Fudan University, Shanghai, 200032, China. [email protected].
  • 6. Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai, 200032, China. [email protected].
  • 7. Department of Oncology, Shanghai Medical College of Fudan University, Shanghai, 200032, China. [email protected].
  • # Contributed equally.
PMID: 38007483 DOI: 10.1186/s13048-023-01286-z
Abstract

Background: Inflammation and immunity are two main characteristics of tumor microenvironment (TME). Interferon-gamma (IFN-γ) is generally considered as a pro-inflammatory cytokine which mediates anti-tumor immune response. Recently, IFN-γ was also reported to play a protumorigenic role. However, the mechanisms of tumor-promoting effect induced by IFN-γ remain unclear.

Methods: The expression of leukocyte antigen-E (HLA-E), IFN-γ, CD3 and CD56 in clinical samples of ovarian Cancer was detected by mutiplexed immunohistochemistry. The mechanism to induce HLA-E overexpression by IFN-γ was explored using human ovarian Cancer cell lines through western blot and flow cytometry. We further clarify the role of overexpressed-HLA-E on natural killer (NK)-mediated Cell Lysis.

Results: We found that IFN-γ could upregulate HLA-E protein expression through activating of JAK/STAT1 signaling pathway, and increase cell surface HLA-E level through enhancing Proteasome activity. We also observed that only high levels of membrane HLA-E expression contributed to the inhibition of NK-mediated cytotoxicity. We showed that progression-free survival (PFS) of ovarian Cancer patients was negatively correlated with IFN-γ expression in their tumor tissues, due to more tumor infiltrating NK cells compared with T lymphocytes.

Conclusions: Our study revealed the protumorigenic role of IFN-γ by upregulation of HLA-E expression and rendering tumors less susceptible to immune attack. We also provided a novel insight into the relationship between tumor microenvironment and immune evasion.

Keywords
Human leukocyte antigen-E; Natural killer cell; Ovarian cancer; Tumor microenvironment.
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