In recent years, a standard follow-up to colorectal cancer surgery has been to analyze the tumour 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. It has been unclear whether the presence of T cells in tumour tissue is just a matter of chance in more benign tumours, or whether the immune cells are specifically and actively responding to the cancer and thus contribute to a more favourable prognosis. Their mere presence does necessarily mean that the body is mounting an immune response against the malignant tissue, because tumours have many ways to inactivate immune cells.
Researchers from the German Cancer Research Center have now collaborated with surgeons from Heidelberg and Dresden University Hospitals to investigate whether the T cells in colorectal tumours are in fact actively fighting the cancer. The opensource study is published in Journal of Clinical Investigation.
Cytotoxic T cells that are activated because they recognize a specific characteristic of the tumour (a tumour antigen) produce a combination of three immune mediators. In particular, activated killer cells produce high levels of tumour necrosis factor (TNF) alpha. The team found high TNF alpha levels exclusively in colorectal tumours from patients in whose blood or bone marrow they could also detect memory T cells that responded specifically to the tumour.
The researchers studied cytotoxic T cells that had been isolated from patient blood or tumour tissue. They discovered that only T cells which were simultaneously activated by specific tumour proteins produced TNF alpha. They found that the total quantity of TNF alpha in the tumour correlated to the number of killer cells producing it.
This was true for tissue samples from 88 colorectal cancer patients, the team asked, could the results be extended to other patients as well? If so, levels of TNF alpha might serve as a valuable, independent biomarker that could be used in a prognosis for the disease. To test the idea, the scientists samples from another 102 bowel cancer patients.
They compared the amount of TNF alpha with other characteristics of tumours that might have an impact on the course of the disease. These included the TNM classification (a way of classifying malignant tumours according to their size, differentiation grade and metastases), the number of regulatory T cells, the number of inflammatory cells that promote tumour growth, and levels of a substance that suppresses immune responses.
The new tissue samples came from 102 patients who had been diagnosed 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 tumour tissue corresponds to the anti-cancer activity of the cytotoxic T cells. This is strong evidence that the prognosis of colorectal cancer patients in fact depends on an active T cell response against the tumour 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 tumour tissue.
The team states that if finding cytotoxic T cells that actively fight the tumour means a good prognosis, it is encouraging evidence for the team’s attempt to develop immunotherapies based on T cells that target colorectal cancer. In the long term the team plan to develop immunotherapies of exactly this kind.