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Role of adhesion molecules in the immune reaction to M-MSV-induced tumors
A Rosato1, V Bronte, S Mandruzzato
1Chair of Immunology, University of Padua, Italy.
Abstract:
We have investigated the in vivo role of 2 different adhesion molecules, LFA-1 and LECAM-1, in the immune reaction to Moloney-murine-sarcoma-virus(M-MSV)-induced tumors, which undergo a peculiar spontaneous regression due to generation of a strong virus-specific cytotoxic-T-lymphocyte(CTL) response. Repeated administration of anti-LFA-1 monoclonal antibody (FD441.8 MAb), i.p. or at the site of virus inoculation, enhanced tumor growth and delayed regression, while i.p. administration of anti-LECAM-1 MEL-14 MAb gave rise to tumors that grew progressively and caused host death. Evaluation of the immunological response in MAb-treated mice showed reduced generation of virus-specific CTL precursors (p) in the spleen of animals given FD441.8 MAb i.p.; CTLp frequency in locally treated mice overlapped with that of control mice injected with virus only. FD441.8 MAb treatment did not interfere with CTL homing in the tumor, since the frequency of M-MSV-specific CTLps in sarcomas was similar in treated and control mice. Cytofluorimetric analysis indicated that the majority of tumor-infiltrating lymphocytes (TIL) from MAb-treated mice were covered by anti-LFA-1 MAb, and lacked cytotoxic activity when assayed against target cells bearing relevant tumor antigens. Instead, in mice injected i.p. with MEL-14 MAb, a very low frequency of CTLps was detected in lymph nodes draining the tumor area, and within the tumor. Our results indicate that enhanced tumor growth, depending on the MAb used, is the resultant of an inhibitory effect on different T-lymphocyte functions. Tumor progression in anti-LFA-1 MAb-injected mice is explained mostly by blockage of CTL lytic activity at the tumor site; in mice receiving i.p. MEL-14 MAb treatment, by the failure of naive T lymphocytes to enter peripheral lymph nodes and subsequently by the lack of generation of tumor-specific CTLs.
Insights
Blocking immune molecules LFA-1 and LECAM-1 hinders anti-tumor responses. Anti-LFA-1 antibody impaired cytotoxic T-lymphocyte (CTL) activity, while anti-LECAM-1 blocked T-cell activation, both promoting tumor growth.
Area of Science:
- Immunology
- Oncology
- Virology
Background:
- Moloney murine sarcoma virus (M-MSV) induces tumors that typically regress via cytotoxic T-lymphocyte (CTL) response.
- Adhesion molecules, including LFA-1 and LECAM-1, play critical roles in immune cell trafficking and function.
Purpose of the Study:
- To investigate the in vivo roles of LFA-1 and LECAM-1 in the immune response against M-MSV-induced tumors.
- To determine how blocking these adhesion molecules affects tumor growth, regression, and the associated CTL response.
Main Methods:
- Mice were inoculated with M-MSV, and then treated with anti-LFA-1 (FD441.8 MAb) or anti-LECAM-1 (MEL-14 MAb) monoclonal antibodies.
- Tumor growth and regression were monitored.
- Immunological responses, including CTL precursor frequency in spleen, lymph nodes, and tumors, were evaluated using cytofluorimetry and functional assays.
Main Results:
- Anti-LFA-1 MAb treatment enhanced tumor growth and delayed regression, primarily by inhibiting CTL lytic activity at the tumor site.
- Anti-LECAM-1 MAb treatment led to progressive tumor growth and host death, attributed to impaired naive T-cell entry into lymph nodes and reduced CTL generation.
- While anti-LFA-1 did not prevent CTL homing to tumors, it reduced their cytotoxic function and impaired CTL precursor generation in the spleen.
Conclusions:
- Both LFA-1 and LECAM-1 are crucial for effective anti-tumor immunity against M-MSV-induced tumors.
- Blocking LFA-1 impairs effector CTL function within the tumor microenvironment.
- Blocking LECAM-1 disrupts the generation of tumor-specific CTLs by hindering T-cell activation and trafficking.