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Tumor immune microenvironment permissive to metastatic progression of ING4-deficient breast cancer.
- Source :
-
PloS one [PLoS One] 2024 Jul 05; Vol. 19 (7), pp. e0304194. Date of Electronic Publication: 2024 Jul 05 (Print Publication: 2024). - Publication Year :
- 2024
-
Abstract
- Deficiencies in the ING4 tumor suppressor are associated with advanced stage tumors and poor patient survival in cancer. ING4 was shown to inhibit NF-kB in several cancers. As NF-kB is a key mediator of immune response, the ING4/NF-kB axis is likely to manifest in tumor-immune modulation but has not been investigated. To characterize the tumor immune microenvironment associated with ING4-deficient tumors, three approaches were employed in this study: First, tissue microarrays composed of 246 primary breast tumors including 97 ING4-deficient tumors were evaluated for the presence of selective immune markers, CD68, CD4, CD8, and PD-1, using immunohistochemical staining. Second, an immune-competent mouse model of ING4-deficient breast cancer was devised utilizing CRISPR-mediated deletion of Ing4 in a Tp53 deletion-derived mammary tumor cell line; mammary tumors were evaluated for immune markers using flow cytometry. Lastly, the METABRIC gene expression dataset was evaluated for patient survival related to the immune markers associated with Ing4-deleted tumors. The results showed that CD68, CD4, CD8, or PD-1, was not significantly associated with ING4-deficient breast tumors, indicating no enrichment of macrophages, T cells, or exhausted T cell types. In mice, Ing4-deleted mammary tumors had a growth rate comparable to Ing4-intact tumors but showed increased tumor penetrance and metastasis. Immune marker analyses of Ing4-deleted tumors revealed a significant increase in tumor-associated macrophages (Gr-1loCD11b+F4/80+) and a decrease in granzyme B-positive (GzmB+) CD4+ T cells, indicating a suppressive and/or less tumoricidal immune microenvironment. The METABRIC data analyses showed that low expression of GZMB was significantly associated with poor patient survival, as was ING4-low expression, in the basal subtype of breast cancer. Patients with GZMB-low/ING4-low tumors had the worst survival outcomes (HR = 2.80, 95% CI 1.36-5.75, p = 0.0004), supportive of the idea that the GZMB-low immune environment contributes to ING4-deficient tumor progression. Collectively, the study results demonstrate that ING4-deficient tumors harbor a microenvironment that contributes to immune evasion and metastasis.<br />Competing Interests: The authors have declared that no competing interests exist.<br /> (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)
- Subjects :
- Animals
Female
Humans
Mice
Cell Line, Tumor
Disease Progression
Neoplasm Metastasis
Breast Neoplasms pathology
Breast Neoplasms immunology
Breast Neoplasms genetics
Cell Cycle Proteins genetics
Cell Cycle Proteins metabolism
Cell Cycle Proteins deficiency
Homeodomain Proteins genetics
Homeodomain Proteins metabolism
Tumor Microenvironment immunology
Tumor Suppressor Proteins genetics
Tumor Suppressor Proteins deficiency
Tumor Suppressor Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 19
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 38968186
- Full Text :
- https://doi.org/10.1371/journal.pone.0304194