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Role of Fas ligand expression in promoting escape from immune rejection in a spontaneous tumor model
D Céfai1, L Favre, E Wattendorf
1Department of Clinical Research, University of Bern, 35 Murtenstrasse, 3010 Bern, Switzerland.
Abstract:
Tumors escape immune-mediated rejection by a variety of mechanisms during tumor progression. The elucidation of these mechanisms in vivo suffers from a lack of suitable models of spontaneous tumor formation escaping active specific immunotherapy (ASI). In a rat neu transgenic (rNeu-TG) mouse model of spontaneous breast tumor formation, we showed that rNeu-TG mice developed late escape tumors despite the presence of a persistent rNeu-specific immune response after ASI. Cell suspensions derived from these escape tumors grew in vaccinated tumor-free mice, whereas injected spontaneous tumor cells were rejected. Escape tumors retained rNeu or MHC class I expression but significantly upregulated Fas (CD95, Apo-1) ligand. We further demonstrated that Fas-L on escape tumor cells correlated with apoptosis of infiltrating T lymphocytes. Thus, our results provide evidence that spontaneous breast tumors upregulate Fas-L expression after vaccination that may promote tumor escape in vivo after ASI.
Insights
Spontaneous breast tumors can evade immunotherapy by increasing Fas ligand expression, leading to T cell death. This mechanism helps tumors escape immune rejection even with a persistent immune response after active specific immunotherapy.
Area of Science:
- Immunology
- Oncology
- Cancer Research
Background:
- Tumors employ diverse strategies to evade immune detection and rejection.
- Effective models for studying spontaneous tumor immune escape after immunotherapy are limited.
- Active specific immunotherapy (ASI) aims to overcome tumor-induced immune tolerance.
Purpose of the Study:
- To investigate mechanisms of immune escape in spontaneous breast tumors following ASI.
- To characterize the immune response and tumor characteristics in a relevant preclinical model.
- To identify molecular factors contributing to tumor resistance to immunotherapy.
Main Methods:
- Utilized a rat neu transgenic (rNeu-TG) mouse model for spontaneous breast tumor development.
- Administered ASI to rNeu-TG mice and monitored tumor progression and immune response.
- Analyzed 'escape' tumors for expression of rNeu, MHC class I, and Fas ligand (Fas-L).
- Assessed the impact of Fas-L on infiltrating T lymphocytes and tumor cell apoptosis.
Main Results:
- rNeu-TG mice developed late-stage escape tumors despite ongoing rNeu-specific immune responses post-ASI.
- Escape tumor cells, unlike spontaneously rejected tumor cells, grew progressively in vaccinated mice.
- Escape tumors maintained rNeu and MHC class I expression but significantly increased Fas-L.
- Elevated Fas-L expression on escape tumor cells correlated with apoptosis of tumor-infiltrating T lymphocytes.
Conclusions:
- Spontaneous breast tumors can develop resistance to ASI through upregulation of Fas-L.
- Fas-L expression on tumor cells promotes immune escape by inducing T lymphocyte apoptosis.
- This study provides a model and evidence for Fas-L mediated immune evasion in breast cancer immunotherapy.