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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
Host perforin reduces tumor number but does not increase survival in oncogene-driven mammary adenocarcinoma
Shayna E A Street1, Nadeen Zerafa, Manuela Iezzi
1Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
Abstract:
The concept of tumor immune surveillance has been supported by several recent studies in mice which show that immune effector mechanisms suppress hematologic malignancy. However, because the most common forms of human cancer are epithelial in origin, and comparatively very little data supports the immune surveillance of epithelial malignancies, we have chosen to evaluate the role of perforin-mediated cytotoxicity in the prevention of BALB/c Her2/neu-induced mammary cancer. Interestingly, perforin significantly delayed the onset of mammary tumorigenesis and reduced the number of mammary tumors without improving survival. Natural killer cell, but not CD8+ T cell, depletion resulted in a similar phenotype to perforin deficiency in this regard. Histologic analysis further indicated that the effect of perforin was most evident during the earliest stages of carcinogenesis rather than prior to or during the hyperplastic phase. This data suggests that perforin may mediate some suppression of epithelial carcinogenesis by intervening early in the tumor development process.
Insights
Perforin-mediated immunity delays mammary tumor development in mice by intervening early in carcinogenesis. This immune surveillance mechanism targets epithelial cancers, suggesting a potential therapeutic target for preventing tumor onset.
Area of Science:
- Immunology
- Oncology
- Cancer Research
Background:
- Tumor immune surveillance is established for hematologic malignancies.
- Limited data exists on immune surveillance of epithelial cancers, the most common human forms.
- Perforin's role in epithelial tumor suppression requires investigation.
Purpose of the Study:
- To evaluate the role of perforin-mediated cytotoxicity in preventing Her2/neu-induced mammary cancer in BALB/c mice.
- To understand the contribution of natural killer (NK) cells and CD8+ T cells to perforin-dependent tumor suppression.
Main Methods:
- Induction of mammary tumors using Her2/neu in BALB/c mice.
- Assessment of tumor onset, number, and survival in perforin-deficient mice.
- Depletion of NK cells and CD8+ T cells to determine their role in perforin's effect.
- Histologic analysis of tumor development stages.
Main Results:
- Perforin significantly delayed mammary tumor onset and reduced tumor incidence, but did not improve survival.
- Depletion of NK cells, but not CD8+ T cells, mimicked the phenotype of perforin deficiency.
- Perforin's suppressive effect was most pronounced during early carcinogenesis, not in pre-cancerous phases.
Conclusions:
- Perforin-mediated cytotoxicity plays a role in suppressing epithelial mammary carcinogenesis.
- The effect appears to be mediated primarily by NK cells.
- Perforin may act by intervening early in the tumor development process, highlighting its potential in cancer prevention strategies.
