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Escape of metastasizing clonal tumor cell variants from tumor-specific cytolytic T lymphocytes
Abstract:
A metastasizing variant of a chemically induced lymphoma from a DBA/2 mouse is shown to carry a distinct tumor-associated transplantation antigen (TATA), which can be recognized by syngeneic secondary anti-tumor cytolytic T lymphocytes (CTL). During metastasis of twice-cloned cell lines of this tumor, variants develop that are specifically immunoresistant to lysis by anti-tumor CTL. The variants are detected in the spleen of normal syngeneic mice. They remain stable over long-term passage in tissue culture. The high frequency with which these immunoresistant metastatic variants develop was found to explain the relative ineffectiveness of specific immunization against this metastatic tumor. Compared with organ-selective metastatic variants, the immunoresistant tumor variants seem to arise with a much higher frequency. The change in TATA expression described here differs from antibody-induced antigenic modulation in that it is more stable and genetically transmitted.
Insights
Metastatic lymphoma variants develop immunoresistance to cytolytic T lymphocytes (CTL). This resistance, driven by changes in tumor-associated transplantation antigen (TATA) expression, explains why cancer vaccines are often ineffective against this tumor.
Area of Science:
- Immunology
- Oncology
- Cancer Metastasis
Background:
- Chemically induced lymphoma in DBA/2 mice exhibits a distinct tumor-associated transplantation antigen (TATA).
- Cytolytic T lymphocytes (CTL) can recognize and target this TATA on lymphoma cells.
Purpose of the Study:
- To investigate the development of immunoresistant variants during metastasis.
- To understand the mechanism behind the ineffectiveness of specific immunization against metastatic lymphoma.
Main Methods:
- Utilized twice-cloned cell lines of a metastasizing lymphoma.
- Detected immunoresistant variants in the spleen of syngeneic mice.
- Maintained variants through long-term tissue culture passage.
Main Results:
- Metastatic variants emerged that were specifically resistant to anti-tumor CTL lysis.
- These immunoresistant variants were detected in vivo and were stable in vitro.
- The high frequency of these variants explains the limited efficacy of specific anti-tumor immunization.
- The observed changes in TATA expression were stable and genetically transmitted, unlike antibody-induced modulation.
Conclusions:
- Immunoresistant variants arise frequently during lymphoma metastasis, contributing to therapeutic challenges.
- Changes in tumor-associated transplantation antigen expression are a key mechanism of immune evasion.
- The stability and genetic transmission of these changes differentiate them from transient antigenic modulation.