Melanomas harbor tumor-recognizing CD4+ T-cells

Source: Netherlands Cancer Institute, December 2014

Immunotherapy is one of the most promising recent developments in cancer treatment. To design successful immunotherapy strategies, knowledge of the way the immune system recognizes and deals with cancer cells is invaluable. Most of the work around immunotherapy focuses on immune cells called CD8+ T cells. Ton Schumacher from the Netherlands Cancer Institute (NKI) has now shown that CD4+ T-cells can also recognize cancer cells and can help trigger the immune response, at least in melanomas. His work was published on December 22 in Nature Medicine.

The body’s own immune system can sometimes recognize and kill cancer cells. Immunotherapy aims to eradicate tumors by enhancing this response. A number of successful immunotherapies have been designed in recent years. However, it is presently still difficult to predict which patients are likely to harbor a tumor-specific immune response that can be enhanced by therapy. Because of this, it is important to understand the rules that allow the immune system to distinguish between healthy cells and cancerous cells.

Cells display at their surface small bits of the proteins that they produce or have taken up. This display of such ‘antigens’ allows the immune system to scan cells for the presence of aberrant proteins that are for instance due to infection of the cell. Most human cancers are not caused by viral infections. However, mutations in the DNA of cancerous cells can also cause them to produce aberrant proteins that can show up as abnormal antigens on the cell surface.

Recent work strongly suggests that the immune response against such mutated antigens is important for the activity of cancer immunotherapy. Most of this work has focused on a subset of immune cells called CD8+ T cells, also known as cytotoxic or killer T cells. However, the immune system harbors another type of T cells termed CD4+ T cells (or ‘T helper cells’) that play an essential regulatory role in the immune response, and their ability to recognize the consequences of DNA damage was largely unknown. Ton Schumacher of the NKI has now shown that CD4+ T cells also frequently recognize human melanoma by the DNA damage they have accumulated. This allows these cells to send out signals to the rest of the immune system to come into action.

For his study, Schumacher and his team screened CD4+ cells that were found inside melanoma tumors for their cancer-recognizing properties by exposing them to all the separate tumor-specific antigens that were present on the melanoma cells. They did so for melanomas of five different human patients with metastatic disease. Four out of five melanomas proved to contain CD4+ T cells with tumor recognizing capabilities. This demonstrates the importance of this type of immune cells for the tumor-specific immune response, and their potential role in cancer immunotherapy.

Schumacher: “These new findings are important, because they give us more insight into the way the immune system can recognize cancer cells. The next step will be to use this knowledge to design immunotherapies that help strengthen the tumor-specific immune response. This will probably be more effective than therapies that broadly activate T cells. In addition, therapies that selectively activate only the tumor-specific T cell pool will likely have less side effects, because the immune system won’t turn against healthy cells."

Schumacher’s team also used the data to predict how often mutations that lead to aberrant proteins that can be seen by CD4+ T cells will be formed in other human cancers.

Schumacher: “Tumor recognition by T cells appears to be a chance process, a bit like the lottery in which the odds you have increase with the number of tickets you bought. The more mutations a tumor cell contains, the more likely it is to carry mutations that can be recognized by the immune system as abnormal. Our study shows that CD4+ T cells are able to recognize melanoma cells that have a mutational load of roughly 10 mutations per megabase of coding DNA."

This mutational load is also present in about 40 percent of lung cancers, 35 percent of uterine cancers, and some 25 percent of colorectal cancers, and this makes them possible candidates for CD4+ T cell based immunotherapies.