When cytotoxic T cells are activated, they produce TNF alpha that helps mediate immune responses. Scientists have now linked rising levels of TNF alpha in tumor tissue to increasing numbers of activated killer cells that specifically recognize the tumor and are capable of fighting it. High levels of TNF alpha in a tumor prove to be an independent prognostic indicator for a favorable course of the disease.
In recent years, a standard follow-up to colorectal cancer surgery has been to analyze the tumor tissue for the presence of immune cells. Finding high quantities of cytotoxic T cells, or “killer cells,” means that there is a good chance that the disease will take a favorable course and that the risk of metastasis is comparatively low.
Whether the presence of T cells in tumor tissue is just a matter of chance in more benign tumors or the immune cells are specifically and actively responding to the cancer and thus contribute to a more favorable prognosis has been unclear. Their mere presence does not necessarily mean that the body is mounting an immune response against the malignant tissue, because tumors have many ways to inactivate immune cells.
Philipp Beckhove, MD, PhD, an immunologist from the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ), has now collaborated with surgeons from Heidelberg and Dresden University Hospitals in Germany to investigate whether the T cells in colorectal tumors are in fact actively fighting the cancer. Their findings were published in the Journal of Clinical Investigation (2014; doi:10.1172/JCI74894).
Cytotoxic T cells that are activated because they recognize a specific characteristic of the tumor (a tumor antigen) produce a combination of three immune mediators. In particular, activated killer cells produce high levels of tumor necrosis factor (TNF) alpha.
The scientists studied cytotoxic T cells that had been isolated from patient blood or tumor tissue. They discovered that only T cells that were simultaneously activated by specific tumor proteins produced TNF alpha. They found that the total quantity of TNF alpha in the tumor correlated to the number of killer cells producing it.
They compared the amount of TNF alpha with other characteristics of tumors that might have an impact on the course of the disease, including the TNM classification (a way of classifying malignant tumors according to their size, differentiation grade, and metastases), the number of regulatory T cells, the number of inflammatory cells that promote tumor growth, and levels of a substance that suppresses immune responses.
The tissue samples came from 102 patients with colorectal cancer diagnosis some time ago, for whom the long-term course of the disease was known. The scientists discovered that high TNF levels were the most reliable indicator of patients who had survived their diagnosis 10 years and who were regarded as cured.
“The TNF level in tumor tissue corresponds to the anticancer activity of the cytotoxic T cells,” Beckhove said. “This is strong evidence that the prognosis of colorectal cancer patients in fact depends on an active T cell response against the tumor cells. What it means is that TNF alpha levels provide a more accurate method of predicting the course of the disease, compared to simply counting the T cells in tumor tissue.”