Scientists at Thomas Jefferson University say they have discovered that a single cell type is actively suppressed in several experimental cancer vaccines. They believe their study (“Selective antigen-specific CD4+ T-cell, but not CD8+ T- or B-cell, tolerance corrupts cancer immunotherapy”), which appears in the European Journal of Immunology, will lead to new methods to break suppression and improve the effectiveness of cancer vaccines.
“The conventional wisdom is that the body knocks out all of the cells that can mount an immune response to the cancer,” said first author Adam Snook, Ph.D., a research instructor at Thomas Jefferson University. “In fact, our work shows that it's only one cell type that is affected. But that cell, the T helper cell, acts as the lynchpin.”
Cancer vaccines are designed to boost the body's natural defenses against cancer. They work by training the immune system to recognize and attack specific tumor peptides, which are a kind of identification tag for tumors. These peptide “tags” help the immune system find and attack cancer cells. There are three types of cells that can “see” and react to these tags: T helper cells, cytotoxic T cells, and B cells, and researchers thought that all three were tolerized to ignore the tags on cancer cells.
Dr. Snook and colleagues tested which cell was involved by inoculating mice with a cancer vaccine they developed for colorectal cancer using a tumor peptide called guanylyl cyclase C (GUCY2C). Normally, GUCY2C-vaccinated mice would not produce much of an immune response from either T-cell type or B cells. However, when the researchers boosted the GUCY2C vaccine by linking it to another peptide called S1 that efficiently activates T helper cells, they were able to see a vigorous activation of cytotoxic T cells and B cells directed at GUCY2C.
In fact, the GUCY2C vaccine-S1 combo improved the survival time of mice with cancer by months compared to only days with GUCY2C vaccine alone. In fact, many mice were cured of their disease.
“Incorporating CD4+ T-cell epitopes from foreign antigens into vaccines against GUCY2C reconstituted CD4+ T-cell help, revealing the latent functional capacity of GUCY2C-specific CD8+ T- and B-cell pools, producing durable antitumor immunity without autoimmunity,” wrote the investigators. “Incorporating CD4+ T-cell epitopes from foreign antigens into vaccines targeting self antigens in melanoma (Trp2) and breast cancer (Her2) produced similar results, suggesting selective CD4+ T-cell tolerance underlies ineffective vaccination against many cancer antigens. Thus, identification of self antigens characterized by selective CD4+ T-cell tolerance and abrogation of such tolerance through self antigen-independent T-cell help is essential for future immunotherapeutics.”
“The results make a lot of sense,” said Dr. Snook. “T helper cells, as their name suggests, provide help to both cytotoxic T cells and to B cells. The entire peptide-specific immune response can be taken out by tolerizing this one cell type.”
In addition, T helper cells are also essential for creating immunological memory. Boosting T-helper cell activation also protected mice from challenge with cancer months after the initial vaccination, increasing their survival and decreasing tumor number.
The next step is to test whether a T-helper peptide-linked GUCY2C vaccine could help fight colorectal cancer in humans. Dr. Snook and colleagues are currently enrolling patients in a clinical trial aimed at reducing the rate of cancer recurrence in patients who had their primary tumors removed.