Повећана експресија GSTA4 у меланому подстиче избегавање антитуморског имунског одговора и повећава метастатски потенцијал
GSTA4 upregulation promotes melanoma immune evasion and metastasis
2023
Authors:
Mojić, MarijaUcche, Sisca
Yokoyama, Satoru
Hayakawa, Yoshihiro
Contributors
Arsenijević, NebojšaDocument Type:
Lecture (Published version)
,
© 2023 by the Serbian Society for Immunology, Molecular Oncology and Regenerative Medicine, Kragujevac, Serbia
Metadata
Show full item recordAbstract:
IFNγ is a crucial cytokine in antitumor immunity. In cancer cells, IFNγ promotes excessive
production of the reactive oxygen species. Oxidative stress leads to DNA damage
and, consequently, triggers cellular senescence or ferroptosis, a type of cell death associated
with increased lipid peroxidation. The IFNγ response defect is commonly observed in
cancers that exhibit immunoevasive properties. This defect is considered a significant factor
contributing to the limited success of cancer immunotherapy in patients with cancer.
In this study, we explored how tumor cells evade the IFNγ-dependent immune response.
We established immune-escape variants of melanoma cells and analyzed changes in their
phenotype. We found that the immune-escape melanoma variants gained resistance to
the IFNγ-induced oxidative stress response. The critical molecule in this process was glutathione-
S-transferase-4 (GSTA4), a member of a family of detoxification enzymes that
play an important role in cellular oxidative stress responses. In addition to the resistance
to IFNγ-mediated antitumor immunity, the immune-escape melanoma variants acquired
higher metastatic ability in vivo by a GSTA4-dependent mechanism. Melanoma patients
with lower expression of GSTA4 had better prognosis in terms of metastasis-free survival
rate. Additionally, melanoma patients with low GSTA4 expression were better responders
to anti-PD1 therapy and showed a better progression-free survival rate.
Our results reveal a novel mechanism by which cancer cells escape from immune
surveillance and increase metastatic potential by developing resistance to oxidative
stress responses through GSTA4 upregulation. Therefore, targeting the oxidative stress
response in cancer cells presents a promising therapeutic approach for overcoming immune
resistance and regulating metastatic progression.
Keywords:
IFNγ; GSTA4; melanoma; immune evasion; metastasisFunding / projects:
- Grant-in-Aid for Scientific Research on Innovative Areas (17H06398 and 21H02783), The Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan, Yasuda Memorial Medical Foundation, the Cooperative Research Project from the Institute of Natural Medicine, University of Toyama
In:
- Arsenijević N, editor. Abstract Book: The second Serbian Molecular Medicine Congress; 2023 Oct 6-8; Foča, Bosnia and Herzegovina. Kragujevac: Serbian Society for Immunology, Molecular Oncology and Regenerative Medicine; 2023. p. 53-5.