GCRC. Germany: When cytotoxic T cells (“killer cells”) are
activated, they produce a protein called tumor necrosis factor alpha
(TNF alpha) that helps mediate immune responses. Scientists from the
German Cancer Research Center in Heidelberg and Dresden University
Hospitals 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.
It has been unclear whether the presence of T
cells in tumor tissue is just a matter of chance in more benign tumors,
or whether the immune cells are specifically and actively responding to
the cancer and thus contribute to a more favorable prognosis. Their mere
presence does necessarily mean that the body is mounting an immune
response against the malignant tissue, because tumors have many ways to
inactivate immune cells.
Professor Dr. Philipp Beckhove, an immunologist
from the German Cancer Research Center (Deutsches
Krebsforschungszentrum, DKFZ), has now collaborated with surgeons from
Heidelberg and Dresden University Hospitals to investigate whether the T
cells in colorectal tumors are in fact actively fighting the cancer.
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. Beckhove's research team found high TNF alpha levels
exclusively in colorectal tumors from patients in whose blood or bone
marrow they could also detect memory T cells that responded specifically
to the tumor.
The scientists studied cytotoxic T cells that had
been isolated from patient blood or tumor tissue. They discovered that
only T cells which 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.
This was true for tissue samples from 88
colorectal cancer patients – 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 tumors that might have an impact on the course of the
disease. These included 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 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 tumor tissue corresponds to the
anti-cancer activity of the cytotoxic T cells,” Beckhove says. “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.”
The immunologist is pleased about the results for
another reason as well. “If finding cytotoxic T cells that actively
fight the tumor means a good prognosis, it is encouraging evidence for
our attempts to develop immunotherapies based on T cells that target
colorectal cancer.” In the long term, Beckhove and his colleagues plan
to develop immunotherapies of exactly this kind.
Christoph Reissfelder, Slava Stamova, Christina
Gossmann, Marion Braun, Andreas Bonertz, Ute Walliczek, Mario Grimm, Nuh
N. Rahbari, Moritz Koch, Maral Saadati, Axel Benner, Markus W. Büchler,
Dirk Jäger, Niels Halama, Khashayarsha Khazaie, Jürgen Weitz, and
Philipp Beckhove: Tumor-specific cytotoxic T lymphocyte activity
determines colorectal cancer patient prognosis. Journal of Clinical
Investigation 2014, DOI: 10.1172/JCI74894