How Cancer Neutralises T Cell Attack

New insights into how tumours neutralise CD8 T cells, and a strategy for overcoming the tumour’s response to attack.

It has long been recognised that the immune system is able to recognise 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 tumours 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, analysed the function of CD8 T cells that recognise 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 recognises; 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 analysed CD8 T cells taken from peripheral blood, subcutaneous metastases, and invaded lymph nodes from patients with metastatic melanoma, was that the tumour seemed to be somehow neutralising the function of the cytotoxic T cells.

“We could clearly identify functional deficits in the T cells isolated from the tumour 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 tumour environment was turning off the activity of the T cells, and suggested to us a mechanism through which the tumours 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 tumour 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 tumour 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 tumour sites. The researchers anticipate that new technologies will need to be developed which enable visualisation of immune effectors by noninvasive means in cancer patients.

We’re still some way from winning the war, but if we can neutralise the tumour’s response to immunological attack we may have one less battle to contend with on the road to victory.

The published study was supported and sponsored by the Ludwig Institute for Cancer Research, under the auspices of the Cancer Vaccine Collaborative. The scientific team was comprised of researchers from: the Lausanne Branch of the Ludwig Institute for Cancer Research, Lausanne, Switzerland; the Multidisciplinary Oncology Center (Centre Hospitalier Universitaire Vaudois), University Hospital Lausanne, Lausanne, Switzerland; Department of Hematology/Oncology at the University of Regensburg, Regensburg, Germany; Swiss Institute for Experimental Cancer Research and National Center of Competence in Research Program on Molecular Oncology, Epalinges, Switzerland; Institute of Immunology and Transfusion Medicine, Ernst-Moritz-Arndt University, Greifswald, Germany.

The Cancer Vaccine Collaborative (CVC) is a partnership between two not-for-profit academic institutions that has developed an unparalleled program that conducts a systematic analysis in humans comparing immunological approaches to the creation of therapeutic cancer vaccines through a coordinated global effort.

The Ludwig Institute for Cancer Research (LICR) is the largest international academic institute dedicated to understanding and controlling cancer. With ten Branches in seven countries, and numerous Affiliates and Clinical Trial Centers in many others, the scientific network that is LICR quite literally covers the globe. The uniqueness of LICR lies not only in its size and scale, but also in its philosophy and ability to drive its results from the laboratory into the clinic. LICR has developed an impressive portfolio of reagents, knowledge, expertise, and intellectual property, and has also assembled the personnel, facilities, and practices necessary to patent, clinically evaluate, license, and thus translate, the most promising aspects of its own laboratory research into cancer therapies.

Since its inception in 1953, the Cancer Research Institute (CRI) has had a singular mission—to foster research that will yield an understanding of the immune system and its response to cancer, with the ultimate goal of developing immunological methods for the control and prevention of the disease. To accomplish these goals, CRI supports scientists at all stages of their careers and funds every step of the research process, from basic laboratory studies to clinical trials testing novel immunotherapies. Guided by a Scientific Advisory Council, which includes four Nobel Prize winners and 24 members of the National Academy of Sciences, CRI awards fellowships and grants to scientists around the world. Additionally, the Institute has more recently taken on a new leadership role in the areas of preclinical and clinical research by serving as the integrating force and facilitator of collaborations among leading experts. CRI has thus become a catalyst for accelerating the development of cancer vaccines and antibody therapies.