Patients with high frequencies of infiltrating CD3+ T
cells within their colorectal tumours have been shown to have a better
5-year survival rate (73%) than those with low levels of CD3+ T
cells (30%) (14
adaptive immune response to colorectal cancers therefore appears
to have an important role in the progression of this disease. However
the role of Treg cells in this process has not yet been defined.
The GIT is considered a 'tolerogenic' organ that responds in
a regulated manner to antigens derived from food and microbes. Consistent
with this chronic exposure to foreign antigens, the GIT is one of
the few normal non-lymphoid tissues where FOXP3+ T cells
have been identified in expression screening using a normal tissue
The frequency of Treg cells within colorectal cancers is probably
controlled by more than one factor. Treg cell numbers may be influenced
by tumour-associated factors that have been reported in other tumours
). For example, Ghiringhelli et
) showed in animal
models that soluble factors secreted by tumour cells injected into
mice and rats converted dendritic cells (DCs) into TGF-β secreting
cells which were capable of inducing Treg cell proliferation. These
tumour-secreted factors have not yet been identified. While this
has not yet been shown with human DCs and tumour lines, a similar
mechanism could explain the increased numbers of Treg cells found
in the peripheral blood, lymph nodes and tumours of cancer patients.
This model would provide an explanation for Treg cell proliferation
in the absence of inflammation and bacteria, as most cancers are
Bacterial translocation across the mucosal surface is increased in
colorectal cancer, possibly due to increased permeability of tight
junctions and by necrosis and ulceration of the tumour surface (27
Bacterial translocation also occurs in both inflammatory bowel disease
) and infective causes of intestinal
inflammation and is thought to be associated with the proliferation
of Treg cells. Makita et al.
) and Maul et al.
) isolated Treg cells from normal
and inflamed colon and showed that they were capable of suppressing
the proliferation and cytokine production of autologous CD4+ CD25-
T cells. Treg cell numbers were increased in the intestinal mucosa
of patients with active inflammatory bowel disease (IBD). However,
this increase was relatively lower than the increase seen in patients with
infective causes of intestinal inflammation, e.g. diverticulitis
). This suggests that the
number of Treg cells in the intestine could be controlled by inflammation.
Maul et al.
suggested that bacterial products such as LPS or flagellin, working
through TLR4 and TLR5 respectively, may be responsible for the increased
numbers of Treg cells seen in these inflammatory gastrointestinal
conditions. TLR4 and TLR5 signalling have been described in murine
Treg cells and LPS shown to stimulate proliferation of Treg cells in
Although a higher number of Treg cells was observed in patients
with advanced versus early disease, this was not statistically significant.
One reason for this may be that the number of patient samples was
too low to reach statistical significance. Alternatively, we cannot
rule out the possibility that the frequency of Treg cells in colorectal
cancer does not vary with the stage of disease, perhaps due to stimuli
from translocated bacteria.
Treg cells were observed in the mucosal lymphoid follicles of both
the normal and malignant colon ().
However, compared with the normal colon where there were fewer Treg cells
in the lamina propria, there was an increase in the number of Treg
cells in the tumour stroma. It is not known whether Treg cells in
vivo exert their function mainly in lymph nodes or in the intestinal
lamina propria. However, it would appear that they are present in
both the mucosal lymphoid follicles and in the stroma of colon cancers
(). Treg cells could therefore
suppress both the induction of an immune response in the lymphoid tissue,
as well as the proliferation and cytotoxic function of effector
cells in the tumour stroma.
In humans it has been shown that denileukin diftitox, a diphtheria
toxin linked IL2 molecule which binds to CD25 and daclizumab, an
anti-CD25 antibody, may be beneficial in some patients with cancer
). They are believed to act
through the elimination of Treg cells, which would then permit the emergence
of an effective anti-tumour immune response. It would be interesting
to see if daclizumab or denileukin diftitox are beneficial to all
cancer patients who have increased numbers of Treg cells or if they
are only beneficial in certain types of cancer.
The results presented here extend the published data on Treg cells
in other malignancies by demonstrating a significant infiltration
of Treg cells into colon carcinomas. This data may prove useful
in the future in targeting patients at high risk of relapse for
more aggressive adjuvant therapy.