New insights into how tumors neutralize CD8 T cells, and a strategy for overcoming the tumorís response to attack.
Lausanne (April 15) -- It has long been recognized that the immune system is able to recognize and destroy cancer cells, but although the immunological battle might slow the progression or spread of cancer, it's usually the cancer that eventually wins the war. Scientists have speculated that this may be because the immune response is not strong enough, or because it does not last long enough to have an effect. Hence the increasing efforts to develop cancer vaccines that induce, strengthen, and increase the duration of immunological attack against cancer cells. However a report published today in Cancer Research has helped to uncover part of the cancer's battle-plan, and suggests new weapons for inclusion in the cancer vaccine arsenal.
In order to understand how tumors escape immunological attack, a team of investigators from the Lausanne Branch of the Ludwig Institute for Cancer Research (LICR), together with collaborators in Switzerland and Germany, analyzed the function of CD8 T cells that recognize a cancer-specific antigen. CD8 T cells are known as cytotoxic or 'killer' T cells because they cause the destruction of cells that display the antigen that the T cell recognizes; in this case, the melanoma-specific Melan-A/MART-1 antigen, which was discovered simultaneously by the LICR and by the NCI. What they found, when they analyzed CD8 T cells taken from peripheral blood, subcutaneous metastases, and invaded lymph nodes from patients with metastatic melanoma, was that the tumor seemed to be somehow neutralizing the function of the cytotoxic T cells.
"We could clearly identify functional deficits in the T cells isolated from the tumor sites," explains Dr. Pedro Romero from the LICR's Clinical Onco-Immunology Group, and a senior author of the study. "In contrast, T cells of the same antigen specificity, but isolated from peripheral blood, appeared functionally competent. This told us that something in the tumor environment was turning off the activity of the T cells, and suggested to us a mechanism through which the tumors might be escaping from the immune system." Essential to these observations was the development of new tools, such as fluorescent tetramers, that enabled the LICR's Tetramer Facility in Lausanne to directly identify antigen specific CD8 T cells.
The Swiss team investigated further and identified two key molecular defects in the CD8 T cells taken from the tumor sites: a reduction of the release of a molecule called interferon gamma, which enhances the stimulation of the immune system; and a reduction in the expression of a protein called perforin, which is essential for cell destruction.
"The important thing for us is that the tumor effects seem to be reversible," says Dr. Romero. "The CD8 cells very quickly lose their defects when we grow them in the laboratory with additional immunological factors called cytokines. The cells are healthy, they proliferate, and their cytotoxic properties are restored."
The team is already conducting early-phase clinical trials of cancer vaccines based on the Melan-A/MART-1 antigen, through its participation in the Cancer Vaccine Collaborative, a partnership between LICR and the Cancer Research Institute based in New York. The LICR scientists will now also investigate how the CD8 T cell findings can be translated into practical application. An immediate consequence of their findings is the need to monitor both the frequency and the functional potential of vaccine induced specific CD8 T cell responses not only in peripheral blood but also at the tumor sites. The researchers anticipate that new technologies will need to be developed which enable visualization of immune effectors by noninvasive means in cancer patients.
We're still some way from winning the war, but if we can neutralize the tumor's response to immunological attack we may have one less battle to contend with on the road to victory.
Source: Eurekalert & othersLast reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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