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Transfer of Manipulated Tumor-associated Neutrophils into Tumor-Bearing Mice to Study their Angiogenic Potential In Vivo
Published on: July 20, 2019
Pro-necrotic molecules impact local immunosurveillance in human breast cancer
Gautier Stoll1,2,3,4, Yuting Ma5,6, Heng Yang5,6
1Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
Abstract:
Necrosis culminates in spilling cellular content through the permeabilized plasma membrane, thereby releasing potentially immunostimulatory molecules in the pericellular space of dead cells. Accordingly, molecules involved in necroptotic signaling, such as receptor-interacting serine/threonine-protein kinase 3 (RIPK3) and mixed lineage kinase-like (MLKL) have been found to stimulate anticancer immune responses in mouse models of chemotherapy. mRNAs encoding prominent pro-necrotic gene products (RIPK1, RIPK3, MLKL, PGAM5 and DFNA5) were correlated with immune-related metagenes in several cancer types (breast, colorectal, lung, ovary, melanoma), revealing the strongest associations in breast cancer. In two independent breast cancer cohorts, the expression of MLKL and DFNA5 was decreased at the mRNA levels in tumor as compared with normal tissues. Moreover, MLKL expression exhibited a strong positive correlation with genes reflecting the presence of B, NK and T lymphocytes in the tumor bed, in multiple distinct breast cancer subtypes. In contrast, the positive correlation between RIPK3 and lymphoid cells was restricted to HER2+ and triple negative/basal-like breast cancer. Moreover, the expression of DFNA5, which mediates post-apoptotic secondary necrosis, mostly correlated with the monocytic lineage and macrophages in ER+/luminal A breast cancers. MLKL (and to some extent RIPK1 and RIPK3) was strongly associated with the local expression of genes involved in interferon-α and interferon-γ responses. Altogether, these results support the idea that pro-necrotic signaling facilitates intratumoral immune responses in human breast cancer.
Insights
Necrosis, a form of cell death, can stimulate anticancer immune responses. Pro-necrotic genes like MLKL and DFNA5 are linked to immune cell presence in breast tumors, suggesting a role in anti-cancer immunity.
Area of Science:
- Immunology
- Oncology
- Cell Biology
Background:
- Necrosis releases immunostimulatory molecules.
- Necroptotic signaling molecules (RIPK3, MLKL) can enhance anti-cancer immunity in mouse models.
- Gene expression of necroptosis-related molecules correlates with immune responses in various cancers.
Purpose of the Study:
- To investigate the association between pro-necrotic gene expression and intratumoral immune responses in human breast cancer.
- To explore the correlation of specific necroptosis pathway genes (RIPK1, RIPK3, MLKL, PGAM5, DFNA5) with immune cell infiltration and interferon responses in breast cancer subtypes.
Main Methods:
- Analysis of mRNA expression data from human breast cancer cohorts.
- Correlation analysis between necroptosis-related genes and immune-related metagenes.
- Examination of gene expression patterns in tumor versus normal tissues.
- Subtype-specific analysis of gene correlations with immune cell markers and interferon responses.
Main Results:
- Pro-necrotic gene expression (RIPK1, RIPK3, MLKL, PGAM5, DFNA5) correlated with immune metagenes, strongest in breast cancer.
- MLKL and DFNA5 mRNA levels were decreased in breast tumors compared to normal tissue.
- MLKL expression positively correlated with B, NK, and T lymphocytes in multiple breast cancer subtypes.
- DFNA5 correlated with monocytic lineage and macrophages in ER+/luminal A breast cancers.
- MLKL, RIPK1, and RIPK3 associated with local interferon-α and interferon-γ response genes.
Conclusions:
- Pro-necrotic signaling pathways are associated with intratumoral immune responses in human breast cancer.
- MLKL and DFNA5 expression may indicate immune infiltration and anti-tumor immunity.
- Necroptosis-related gene expression patterns vary across breast cancer subtypes and correlate with specific immune cell types and responses.
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