While cancer is a disease that is characterized by an unchecked production of cells, it appears in the body in many variations. Leukemia and lymphoma are two types of cancer that strike cells that are key in the formation of blood. Abnormal cells created by these cancer types circulate through the bloodstream and the lymphatic system and disrupt the functions of those systems, but they may also invade other bodily organs and systems and form additional tumors throughout the body.
Lymphoma and leukemias result from the unrestrained growth of one type of B cell or T cell that usually defends the body against disease, but which can also mutate into tumor cells. The La Jolla Institute for Allergy & Immunology research laboratories are finding more effective ways to focus the immune system's natural attack cells, killer T cells, to create immunotherapies and to vaccinate against specific cancer types.
“I genuinely believe these are cancers we can do something about,” said Stephen Schoenberger, Ph.D. “Lymphoma and leukemias are perplexing because these tumors are found within the very organs (spleen and lymph nodes) in which immune responses are initiated. And yet they evoke no apparent response.”
Schoenberger believes that this lack of response is caused by a special mechanism that enables the cancerous B and T cells to induce a process termed tolerance in killer T cells – effectively stopping the killer cells from destroying them. Schoenberger is investigating possible ways of inhibiting the tolerance mechanism, so that cancerous B or T cells can be destroyed. Our researchers are focused on a subset of T cells called “killer” (cytotoxic) T lymphocytes (CTL). Properly controlled, CTL can confer protective immunity to a wide variety of infectious organisms and can even be instructed to attack tumors or latent viruses that attempt to hide from the immune system. Loss of CTL regulation, however, can result in unwanted destruction of healthy tissue and pathogenic autoimmunity. The laboratory is trying to understand the rules by which CTL are activated and regulated, and the degree to which they can be harnessed for therapeutic goals.
Michael Croft, Ph.D. is focused on increasing the growth and survival of T cells to give the body a fighting chance against cancer. “The concept is that all diseases are controlled by T cells,” said Croft. “My lab works on the molecules that regulate T cells – what makes them work better or work worse.”
In the setting of cancer, the body’s immune cells don’t efficiently target a cancer cell – the tumor – because they are normal cells always present in the body, and the body is resistant to reacting against itself. Cancer cells start dividing and the best way to stop them — the immune system — is weakened.
“T cells can target and kill cancer cells but they don’t normally want to do that. One of the potential strategies in cancer immunotherapy is to make the T cell react to the tumor cell,” said Croft. “Some of the molecules we work on are molecules that can potentially stimulate a T cell to make it work better and make it attack the tumor cell (the cancer).”
There is a delicate balance between factors that affect the lifespan and functionality of a T cell, factors that are controlled by specific proteins expressed on the surface of the cell. “A part of what we do is to understand what happens when these proteins are triggered, what happens within the cell that somehow either induces death, or otherwise affects the lifespan of the cell,” said Croft. In the case of cancer, the idea is for the T cell to live longer than normal so it can attack the tumor cell. Tumors produce proteins that they express on their surface that kill T cells as well as make secreted proteins that also block a T cell from being active. This is a benefit to the tumor cell because these proteins allow the tumor to keep growing. To improve the body’s anti-tumor response, you must allow the T cell to live in the face of proteins created by the tumor to kill it or suppress it.
La Jolla Institute for Allergy & Immunology researchers are investigating the roles of protein molecules expressed on T cells in several diseases, including asthma, multiple sclerosis, diabetes, and cancer to determine if they could be potential targets for therapeutic intervention. Specifically, researchers are working on a number of protein molecules that are members of the tumor necrosis factor receptor (TNFR) super-family, a group of proteins believed to play an important role in the ability of the immune system to guard the body against harmful microorganisms. However, these proteins are also highly relevant to tumor immunology, and understanding how they control the ability of a T cell to grow and survive and target a tumor may lead to novel therapies for cancer.
Three molecules being studied extensively are named OX40, 4-1BB, and TRAIL. Recent data shows that signals from these molecules control the activities and long-term survival of T cells. One line of research is investigating whether substances that can signal T cells through OX40 and 4-1BB can be used to increase natural immune responses, while another line is determining whether substances that can block the activity of TRAIL can also allow a more effective immune response. This is particularly important for diseases such as cancer, in which T cells do not function strongly against the growing tumor.
