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Updated: Aug 30, 2026
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Published on: June 12, 2021
The influence of CD95L expression on tumor rejection in mice
Frederik H Igney1, Christian K Behrens, Peter H Krammer
1Tumor Immunology Program, German Cancer Research Center, Heidelberg, Germany.
Abstract:
Many tumors express the death ligand CD95L (CD178, APO-1L, FasL) and can kill activated T cells in vitro. This may enable the tumor cells to suppress anti-tumor immune responses, a phenomenon called "tumor counterattack". Preliminary evidence of tumor counterattack in human tumors exists. However, CD95L-expressing tumors are rapidly rejected in mice. In order to clarify this controversial situation we investigated whether the level or the time point of CD95L expression might be critical factors determining tumor counterattack versus tumor rejection. We generated CD95-resistant tumor cell lines expressing different levels of CD95L (LKC-CD95L). In nude mice the CD95L expression level had no influence on the growth of the CD95L(+) tumors. In contrast, a CD95L(-) control tumor cell line (LKC) grew much faster. In addition, we generated a CD95-resistant cell line in which CD95L was induced via the tet system (LKCR-tetCD95L). Induction of CD95Lin established tumors in nude and NOD/SCID mice led to rapid rejection of the tumors. Induction of lower CD95L expression levels delayed tumor rejection only marginally. These results demonstrate that rejection of CD95L-expressing tumors in mice is not a result of overexpression and does not depend on the presence of CD95L at the onset of tumor progression.
Insights
Tumor cells expressing CD95L can suppress immune responses. However, CD95L-expressing tumors are rejected in mice, suggesting timing and level of CD95L expression are critical for tumor immune evasion or rejection.
Area of Science:
- Immunology
- Cancer Biology
- Tumor Microenvironment
Background:
- Tumors expressing CD95L (FasL) can kill T cells, potentially suppressing anti-tumor immunity (tumor counterattack).
- CD95L-expressing tumors are paradoxically rejected in mice, contrasting with potential immune suppression in humans.
Purpose of the Study:
- To investigate if CD95L expression level or timing determines tumor counterattack versus rejection.
- To clarify the role of CD95L in tumor immune evasion and rejection in a mouse model.
Main Methods:
- Generated CD95-resistant tumor cell lines with varying CD95L expression levels (LKC-CD95L).
- Utilized a tet-inducible system (LKCR-tetCD95L) to control CD95L expression in established tumors.
- Assessed tumor growth and rejection in nude and NOD/SCID mice.
Main Results:
- CD95L expression level did not influence tumor growth in nude mice; CD95L-negative tumors grew faster.
- Induction of CD95L in established tumors led to rapid rejection, irrespective of mouse strain.
- Lower CD95L induction levels only marginally delayed tumor rejection.
Conclusions:
- Tumor rejection in mice is not due to CD95L overexpression.
- The presence of CD95L at the onset of tumor progression is not essential for rejection.
- Tumor counterattack versus rejection depends critically on the timing and level of CD95L expression.
