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Functional analysis of Ran/TC4 as a protein regulating T-cell costimulation
J D Nieland1, M C Haks, B L Kremers
1Division of Immunology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Huis, Amsterdam.
Cancer Gene Therapy
|November 21, 1998
Summary
Tumor cells lacking CD80/CD86 can still costimulate T cells. Overexpression of Ran/TC4 in tumor cells confers costimulatory function for CD8 T cells, enabling tumor rejection and suggesting novel cancer therapy applications.
Area of Science:
- Immunology
- Molecular Biology
- Oncology
Background:
- T-cell activation requires T-cell receptor and costimulatory receptor engagement (e.g., CD28).
- Tumors often lack CD80/CD86 ligands for CD28, yet some can still costimulate T cells.
- The molecular basis for T-cell costimulation by CD80/CD86-negative tumors is unclear.
Purpose of the Study:
- To identify molecular mechanisms underlying T-cell costimulation by tumors lacking CD80/CD86.
- To investigate the role of Ran/TC4 in tumor cell-mediated T-cell costimulation.
Main Methods:
- Screening a tumor cell line cDNA library for costimulatory activity using COS cell transfection.
- Transfecting Ran/TC4 into the murine RMA lymphoma cell line.
- Assessing in vivo tumor growth and T-cell responses in mice.
Main Results:
- Ran/TC4 overexpression conferred costimulatory activity for CD8 T cells, not CD4 T cells.
- Ran/TC4 transfection into RMA cells induced CD8 T-cell costimulation and protection against tumor growth.
- Ran/TC4-mediated tumor rejection involved T and/or B cells, with cytotoxic T-cell responses against both transfected and wild-type tumor cells.
Conclusions:
- Gene transfer-mediated elevation of Ran/TC4 confers CD8 T-cell costimulatory function to tumor cells.
- Ran/TC4 represents a novel target for regulating tumor cell costimulation and enhancing anti-tumor immunity.