Apoptosis
Cell adhesion
Immunology
Signal Transduction
Cancer Immunology

A major pathway for the elimination of T lymphocytes during the resolution of an immune response is the Fas/Fas-Ligand apoptotic pathway. In Autoimmune and chronic inflammatory diseases such as rheumatoid arthritis, this pathway is defective and as a result, large numbers of T lymphocytes accumulate in the inflammatory sites to perpetrate the inflammatory response. Our goal is to determine the mechanisms by which T lymphocytes become resistant to death via the Fas/Fas-L pathway .T lymphocytes express several members of the beta 1 integrin family that play a role in T cell adhesion and costimulation. In addition to their role in cell adhesion, integrins can also protect from apoptosis and may therefore constitute an important pathway in resistance to apoptosis. In T lymphocytes, we have recently demonstrated that integrin; a collagen receptor, protects from the Fas/Fas-Ligand pathway (1). The objectives are to determine the molecular mechanisms by which integrin signaling modulates the Fas death pathway. and determine how these mechanisms contribute to inflammatory diseases such as rheumatoid arthritis.

This project is supported by the Canadian Institutes
of Health Research (CIHR), the Fonds de la
Recherche en Santé du Quebec (FRSQ) and the Canadian Arthritis Network (CAN).

A second aspect of this project is to understand how integrin signaling regulates chemo-resistance. One of the most important advances in oncology is the treatment of cancer with chemotherapy. However, many patients develop recurrent disease and become refractory to any kind of chemotherapy due to the development of drug resistance. This is particularly the case with leukemia and lymphoma. Most chemotherapeutic drugs (chemo-drugs) exert their cytotoxic effects by inducing apoptosis suggesting that tumor cells acquire drug resistance by acquiring a resistance to apoptosis. Our goal, similar to the regulation of Fas death pathway in T lymphocytes, is to define the role of integrin signaling in the modulation of drug-induced apoptosis and its contribution to the development of drug resistance in lymphoma/leukemia cells.

This project is supported by
the Canadian Institutes of Health Research (CIHR)
and the Fonds de la Recherche en Santé du Quebec (FRSQ).

Tumor escape has been associated with the ability of cancer cells to take advantage of a variety of strategies for evading immune detection and killing. Melanoma tumors arise from pigment producing melanocytes and represent the most lethal type of cutaneous cancers. In contrast to melanocytes, melanoma cells express constitutively the MHC class II molecules, known as the antigen presenting molecules, and are capable of presenting the tumoral antigen to specific T lymphocytes. Despite this recognition, the immune system fails to eliminate the melanoma cells, which progress towards a more malignant phenotype. We have made the observation that during interactions of melanoma cells with lymphocytes, signals transmitted through MHC class II molecules could promote the survival of melanoma cells and thereby contributing to their progression. The objectives of this project are to determine the mechanisms by which MHC class II signaling promote melanoma cell survival with the goal to identify new targets that will help the development of more efficient immunotherapeutic protocols.

This project is supported by
the Cancer Research Society.