Tumor cell cytoplasmic metallothionein expression associates with differential tumor immunogenicity and prognostic outcome in high-grade serous ovarian carcinoma
- PMID: 38023247
- PMCID: PMC10663300
- DOI: 10.3389/fonc.2023.1252700
Tumor cell cytoplasmic metallothionein expression associates with differential tumor immunogenicity and prognostic outcome in high-grade serous ovarian carcinoma
Abstract
Background: The underlying mechanism of high T-cell presence as a favorable prognostic factor in high-grade serous ovarian carcinoma (HGSOC) is not yet understood. In addition to immune cells, various cofactors are essential for immune processes. One of those are metallothioneins (MTs), metal-binding proteins comprising various isoforms. MTs play a role in tumor development and drug resistance. Moreover, MTs influence inflammatory processes by regulating zinc homeostasis. In particular, T-cell function and polarization are particularly susceptible to changes in zinc status. The aim of the present study was to investigate a possible role of MT-mediated immune response and its association with prognostic outcome in ovarian cancer.
Methods: A retrospective study was conducted on a clinically well-characterized cohort of 24 patients with HGSOC treated at the University Hospital of Essen. Gene expression patterns for anti-cancer immunogenicity-related targets were performed using the NanoString nCounter platform for digital gene expression analysis with the appurtenant PanCancer Immune Profiling panel, consisting of 770 targets and 30 reference genes. Tumor-associated immunohistochemical MT protein expression was evaluated using a semi-quantitative four-tier Immunohistochemistry (IHC) scoring.
Results: MT immunoexpression was detected in 43% (10/23) of all HGSOC samples. MT immunoexpression levels showed a significant association to survival, leading to prolonged progression-free and overall survival in positively stained tumors. Furthermore, T-cell receptor signaling gene signature showed a strong activation in MT-positive tumors. Activated downstream signaling cascades resulting in elevated interferon-gamma expression with a shift in the balance between T helper cells (TH1 and TH2) could be observed in the MT-positive subgroup. In addition, a higher expression pattern of perforin and several granzymes could be detected, overall suggestive of acute, targeted anti-cancer immune response in MT-positive samples.
Conclusion: This is the first study combining broad, digital mRNA screening of anti-tumor immune response-associated genes and their relation to MT-I/II in ovarian cancer. MT overexpression is associated with molecular characteristics of an anti-cancer immune response and is a strong prognostic marker in ovarian HGSOC. The observed immune cell activation associated with tumor MT expression comprises but is not limited to T cells and natural killer cells.
Keywords: high-grade serous ovarian carcinoma; immune response; metallothionein; overall survival; zinc signaling.
Copyright © 2023 Mairinger, Wessolly, Buderath, Borchert, Henrich, Mach, Steinborn, Kimming, Jasani, Schmid, Bankfalvi and Mairinger.
Conflict of interest statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Figures
![Figure 1](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/10663300/bin/fonc-13-1252700-g001.gif)
![Figure 2](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/10663300/bin/fonc-13-1252700-g002.gif)
![Figure 3](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/10663300/bin/fonc-13-1252700-g003.gif)
![Figure 4](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/10663300/bin/fonc-13-1252700-g004.gif)
![Figure 5](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/10663300/bin/fonc-13-1252700-g005.gif)
Similar articles
-
Digital Immune-Related Gene Expression Signatures In High-Grade Serous Ovarian Carcinoma: Developing Prediction Models For Platinum Response.Cancer Manag Res. 2019 Nov 12;11:9571-9583. doi: 10.2147/CMAR.S219872. eCollection 2019. Cancer Manag Res. 2019. PMID: 31814759 Free PMC article.
-
Clinicopathological study of metallothionein immunohistochemical expression, in benign, borderline and malignant ovarian epithelial tumors.Histol Histopathol. 2006 Apr;21(4):341-7. doi: 10.14670/HH-21.341. Histol Histopathol. 2006. PMID: 16437378
-
Increased expression of IDO1 is associated with improved survival and increased number of TILs in patients with high-grade serous ovarian cancer.Neoplasia. 2023 Oct;44:100934. doi: 10.1016/j.neo.2023.100934. Epub 2023 Sep 11. Neoplasia. 2023. PMID: 37703626 Free PMC article.
-
Metallothioneins in human tumors and potential roles in carcinogenesis.Mutat Res. 2003 Dec 10;533(1-2):201-9. doi: 10.1016/j.mrfmmm.2003.07.013. Mutat Res. 2003. PMID: 14643421 Review.
-
Clinicopathological significance of metallothioneins in breast cancer.Pathol Oncol Res. 2004;10(2):74-9. doi: 10.1007/BF02893459. Epub 2004 Jun 9. Pathol Oncol Res. 2004. PMID: 15188022 Review.
References
LinkOut - more resources
Full Text Sources