REVIEW
T cells in tumor microenvironment
Yağmur Kiraz
1,2
& Yusuf Baran
1,2
& Ayten Nalbant
1
Received: 4 August 2015 /Accepted: 12 October 2015 /Published online: 18 October 2015
#
International Society of Oncology and BioMarkers (ISOBM) 2015
Abstract Tumors progress in a specific area, which supports
its development, spreading or shrinking in time with the pres-
ence of different factors that effect the fate of the cancer cells.
This specialized site is called Btumor microenvironment^ and
has a composition of heterogenous materials. The immune
cells are also residents of this stromal, cancerous, and inflam-
matory environment, and their types, densities, or functional
differences are one of the key factors that mediate the fate of a
tumor. T cells as a vital part of the immune system also are a
component of tumor microenvironment, and their roles have
been elucidated in many studies. In this review, we focused on
theimmunesystemcomponentsbyfocusingonTcellsand
detailed T helper cell subsets in tumor microenvironment and
how their behaviors affect either the tumor or the patient’s
outcome.
Keywords Tcells
.
Thelpercells
.
Th17 cells
.
Cancer
immunology
.
Tumor microenvironment
Tumor microenvironment
The development and propagation of cancer depend on not
only cancer cells and cancer stem cells within tissue but also
other necessary components, which can be named as cancer
microenvironment that is regarded as cancer bed and involves
many kinds of resident and non-resident constituents [1, 2].
Cancer as a very complex disease includes both the trans-
formed cells and non-transformed cells as host stromal cells
that involve endothelial cells, fibroblasts, immune cells, and
complex extracellular matrix [3]. Cancer microenvironment
that is composed of resident components as stromal cells
and non-resident components as various kinds of immune cell
populations is the major factor that determines the fate of
cancer such as the prevention or encouraging the cancer initi-
ation, metastasis and invasion, and angiogenesis [4]. It can be
definitely said that any change that happens in the epithelial
cells which also would result in changes in the stromal cell
integrity affects and alters the characteristics and initiation of
cancer in the way of it can promote invasion and metastasis
[5]. As it is expected, those changes can be resulted from the
abnormalities in the blood vessels that feed up the tumor cells.
It also affects the amount of molecules, which are necessary
for the normal metabolic reactions, and normal host cells that
are found close to tumors, which begin to malignant tumors
and gain the ability to spread among tissues. So, there is a
reciprocal relationship between tumor microenvironment and
malignant tumor cells as tumor cells can change its microen-
vironment and determine its characteristics. Additionally, tu-
mor microenvironment can promote or prevent the initiation
and propagation of cancer within tissues and body. The com-
position and characteristics of the tumor microenvironment
can be different between the different kinds of cancer or be-
tween patients that have same type or even subtype of cancer.
For example, as expectedly, solid tumors have different
Yağmur Kiraz, Yusuf Baran and Ayten Nalbant contributed equally to this
work.
* Ayten Nalbant
aytennalbant@iyte.edu.tr
1
Department of Molecular Biology and Genetics, Molecular
Immunology and Gene Regulation Laboratory, Izmir Institute of
Technology, Urla, 35430 İzmir, Turkey
2
Faculty of Life and Natural Sciences, Abdullah Gul University,
38080 Kayseri, Turkey
Tumor Biol. (2016) 37:39–45
DOI 10.1007/s13277-015-4241-1
microenvironment components from the hematologic malig-
nancies. Besides, there can be observable difference in the
composition of immune cell types as T and B cells for the
same cancer type [6]. In this review, after brief explanation
about the general properties of tumor microenvironment, the
composition of this tumor microenvironment will be focused
and considered in details. Majority of T cells and their subsets
on the cancer will be evaluated in details in addition to their
action mechanisms against different types of tumors. As a part
of their dual-face phenomenon in tumors, T
H
17 cells as well
as T
reg
cells will be considered as main players of immune
system attack or failure against cancer. This review will be
helpful to the researchers who study on tumor microenviron-
ment and are interested in the roles of immune system cells on
cancer-specific niche.
Immune cells in tumor microenvironment
As mentioned before, there are different kinds of non-
transformed components of tumor microenvironment as the
stromal cells. As it is expected, carcinogenesis is aff ected not
only by the e pithelial cells but also by the other types of cells
such as inflammatory cells, fibroblasts, and immune cells such
as dendritic cells and macrophages [1, 7]. Angiogenesis, which
is an essential phenomenon for the initiation of cancer and
propagation as metastasis, provides the transportation of neces-
sary molecules for the growth of cancer cells such as oxygen
and nutrients between normal blood vessels and tumor cells by
the formation of special vessel for cancer cells. For this reason,
the formation of an giogenesis depends on the existence of en-
dothelial cells in the tumor microenvironment [1, 8].
Cancer-associated fibroblasts (CAFs) are another impor-
tant component of tumor microenvironment and in this envi-
ronment; those fibroblasts are specific for the cancer cells. In
this environment, they act as a regulatory component of tumor
cells’ specific phenomena such as metastasis, carcinogenesis,
and therapy resistance and they can include mesenchymal
cells, endothelial cells, and epithelial cells as a heterogeneous
population [1, 9–11]. Those CAFs as prominent regulatory
components are also regulated by cancer cells in terms of with
some activator molecules [4]. In addition to those resident
components of tumor microenvironment, there are also non-
resident components that specify the characteristics of this
microenvironment as dendritic cells, cancer-associated mac-
rophages, T lymphocytes, B lymphocytes, and natural killer
cells [3]. As it is known, many kinds of immune cells are
responsible for the formation of immune response that can
prevent or inhibit the initiation of cancer or propagation. The
immune cells also play roles on invasion and metastasis within
the different tissues, and those immune cells are carried to
related site by cancer-related blood vessels and/or extravasa-
tion [12]. In many cases, this response can be achieved by host
immune system when the cancer development is at early stage
and while it cannot control its microenvironment effectively.
However, when the tumor growth reaches the specific late
stages, immune system cannot achieve the effective immune
responses because of the immunosuppressive mechanisms of
cancer cells and the high ability to control their microenviron-
ment [3].
For many years, it was expected that all types of macro-
phages are responsible for fighting with cancerous cells; how-
ever, it is understood that some kinds of them can promote the
initiation and propagation of cancer cells by forming specific
cancer-associated macrophages [13]. Besides, they can pro-
duce immunosuppressive cytokines to prevent the necessary
immune response and promote the angiogenesis by producing
some necessary molecules [14]. On the other hand, dendritic
cells which are the known best antigen-presenting cells in the
immune system with their capability of present peptides
through both MHC class I and MHC class II molecules are
also involved in the regulation of immune response against
tumor cells [3, 15]. The most advantageous feature of dendrit-
ic cells is the cross presentation system that leads to the acti-
vation of immune cells by two different paths: those of one,
through the presentation of antigens to cytotoxic T cells by
MHC class I molecules and thepresentation of the antigens by
MHC class II at the same time, in order to get an efficient
response from the immune system against the tumor [3]. In
addition, there is another cell type as natural killer cells that
belong to immune system and they share similar surface re-
ceptors with macrophages. However, there are additional
kinds of surface receptors for natural killer cells and those
cells have essential responsibilities to fight against tumor cell
growth by some special surface receptor on natural killer cells
[16, 17]. Those receptors are very important to sustain host
cancer immune response against tumor initiation [18]. Fur-
thermore, natural killer cells are accepted as dendritic editing
cells to destroy partially immature dendritic cells (DCs) and
inhibit their un-preferable functions inside the cells as
inhibiting the activity of tolerogenic DCs and facilitating to
maintain anti-tumor response [19–21
]. In addition, extracellu-
la
r matrix (ECM) can affect the fate of tumor. ECM estab-
lishes the direct contact with newly forming cancer cells and
it can promote the conversion to malignant tumor and metas-
tasis by majorly supporting the secretion of different cytokines
[1, 22](Fig.1).
T lymphocytes in tumor microenvironment
T lymphocytes are abundant components of tumor microen-
vironment, and they are named as tumor-infiltrating lympho-
cytes in terms of existing close to growing tumor cells and
forming special lymphocytes for cancer cell microenviron-
ment [23]. In the microenvironment of all kinds of cancer,
40 Tumor Biol. (2016) 37:39–45
there are an increasing number of related tumor-infiltrating
lymphocytes (TILs) in patients while only one kind of TIL
cells can exhibit the necessary response against cancer cells as
anti-cancer activity [3, 12]. As it is known, malignant cells are
antigenic and produce specific antigens that are recognized
andidentifiedbyimmunecells(antigen-presentingcells)
and introduced to host T cells (T lymphocytes) that can be
defined as a part of cell-mediated immune system [24]. Al-
though those antigens are used to activate host immune sys-
tem to disrupt cancer cells or inhibit metastasis by activity of T
cells, there can be a controversy as immune cells can promote
the growth or propagation of cancerous cells [12]. T cells
involve two main classes of immune cells as CD4+ and
CD8+ [25]. Those cells are both responsible for the perfor-
mance of anti-cancer activity. However, the type of CD8+
cells is named as cytotoxic T cells and they have the capability
to kill and disrupt the target cells by the help of granzyme B
and perforin which endow cytotoxic and apoptotic activity for
those cells [3, 12]. In addition to them, there is a supporter
molecule type for the activity of CD8+ as interferon gamma
(IFN-γ), which is also produced by themselves [3]. The gen-
eral principles and role of CD8+ in the tumor microenviron-
ment have been worked with UV-induced skin cancer mouse
models, chemically induced papilloma, and retoncogene
transgenic model of spontaneous melanoma to figure out the
importance of CD8+ cells for the immunosurveillance as the
response for the growing tumor and metastasis [3, 26–28].
The high amounts of CD8+ in the circulating system signify
the existence of an abnormality/foreign material that should be
eliminated in a host system. This situation is clearly promoted
by the researches in patients with metastatic melanoma [3,
29]. After cancer cells are induced to be exposed to apoptosis,
they constitute apoptotic bodies, which have the capabilities to
induce tumor-infiltrating DCs to convert naive T cells t o
active/mature state. This tumor-specific immunosurveillance
is achieved with those apoptotic bodies by moving them
through lymph nodes and other different lymphoid organs
and introducing the tumor-specific antigens to the other T cells
[30–32](Fig.2).
Furthermore, the patients having the higher amo unt of
tumor-infiltrated T cells were shown that they tend to exhibit
good prognosis compared to the rest of the patients in various
types of cancer including breast, lung, or colon [33, 34]. Tu-
mor microenvironment generally provides suitable conditions
for the cytotoxic activity of cytotoxic T lymphocytes (CTLs).
Though, the activity of CTLs is affected by some factors,
which are specified by different sources as tumor microenvi-
ronment by itself or tumor cells. These factors can be summa-
rized as follows: (i) the amount of cytokines or chemokines
which are released by the cells found in tumor microenviron-
ment, (ii) the ability of tumor cells to escape from the cyto-
toxic activity of T cells by molecular plasticity, and (iii) be-
havior of the interactions between TCR and MHC molecule
which can be exemplified by the situation of melanoma cells
which are shown as having the reduced level of MHC-1 mol-
ecule expression on the surface of APC. Therefore, this situ-
ation prevents the recognition of specific antigens by DCs,
introduces them to T cells, and lowers the further immune
response [3, 35].
T
H
1andT
H
2 cells in tumor microenvironment
In addition to cytotoxic T cells, there is another class of T cells
as CD4+, which acts as helper cells and modulates the
Fig. 1 Different cell types such as dendritic cells, macrophages,
fibroblasts, and lymphocytes are found in a typical tumor
microenvironment. The tumor mass is also feed by vascularization also
known as angiogenesis in a malign way. The composition of each cell
differs in each cancer types or between patients. The density of different
cells also affects the outcome of the disease that was also detailed in the
text
Tumor Biol. (2016) 37:39–45 41
activation of CTLs. There are four main classes of helper T
cells that have been separated from each other according to
their effects within host immune system as T
H
1, T
H
2, T
H
17,
and T
reg
, and the transition is driven by the amount and the
type of the cytokines in the environment [6, 36]. CD4+ cells
can cause anti-cancer immune response by producing related
cytokines to stimulate CD8+ with the activity of T
H
1andT
H
2
helper T cells. They also have the capability to facilitate the
activation of CD8+ and improve the destroying capacity of
those cells and macrophages. T
H
1 can achieve this activation
of macrophages and CD8+ by producing IFN-γ,TGF-β,and
IL-2 cytokines while T
H
2 helper T cells have different kinds of
cytokines and target immune cells. Specific cytokines can be
listed as IL-4, IL-5, and IL-6 to facilitate B cell proliferation
and antigen production [6]. For the bacterial and viral infec-
tion and allergic or atopic inflammations, those T
H
1andT
H
2
helper T cells are dominant in the host. The responsibility of
these T
H
1andT
H
2 helper T cells is not restricted with only
CD8+ stimulation, as it is shown that in a study from 1998,
those cells are very important for anti-tumor immunity [37].
For example, macrophages that are stimulated by the activity
of T
H
1 cytokines produce nitric oxide that can perform as an
anti-cancer agent. Besides, activation of DCs can also be
achieved by the secretion of IFN-γ from the T
H
1 cells. These
cytokine molecules increase the level of IL-12, which is relat-
ed with activation of DCs, and as a result, those activated DCs
can stimulate the CTLs [38–40]. As said before, T
H
2 cells are
common helper T cells for the response to allergic inflamma-
tions and extracellular pathogens; however, those cells are
also important for the tumor immunity which are related with
the special molecule as eosinophils. These molecules are re-
cruited by the T
H
2 helper T cell and show the capability to
destroy cancer cells by their specific cytotoxic protein prod-
ucts [37, 41].
T
H
17 cells in tumor microenvironment
T
H
17 is another subtype of CD4+ cells, which are basically
responsible for the autoimmunity, controversial tumor immu-
nity, disrupting immune tolerance, and response against extra-
cellular bacteria. T
H
17 cells are referred as the most special
helper T cell subset since they either can promote or can pre-
vent cancer cell growth and metastasis with different subsets
and various cytokines that are produced by those subsets
[42–44]. Their differentiation depends on the coming signals
and existing cytokines in the environment. These T
H
17 cells
can be differentiated into T
H
1 if there are necessary cytokines
for the differentiation as IL-12 and newly forming T
H
1cells
loss their ability to secrete IL-17 and get the ability to produce
and secrete IFN-γ. The increasing amount of T
H
1 T helper
cells can facilitate the stimulation of CD8+ cells and can assist
in destroying cancer cells [42].
In addition to this, immune response can be improved by the
specific factors as granulocyte-macrophage colony-stimulating
factors (GM-CSF) that are produced by those T
H
17 cells in
cancer patients. Also, there are other produced cytokines as
tumor necrosis factor alpha (TNF-α), IL-2, and IFN-γ, but no
IL-10. T
H
17 specifically those cytokines can behave like the
cytokines that are produced during the viral infections, and
those cytokines have the capability to influence and mediate
local cancer immune response that is showed against cancer. As
said before, there are specific cytokines that are produced in
different cancer patients as melanoma, breast, and colon can-
cers which produce T
H
17 cells in microenvironment that se-
crete IL-8 and TNF-α, but not IL-2 [42, 45].
ThebehaviorofthoseT
H
17 cells can be specified in tumor
microenvironment according to the cancer type or the coming
signal from environment or cancer tissue. T
H
17 cells can be-
have controversial, as they can act for improvement of anti-
Fig. 2 After tumor antigen is
presented to dendritic cells, DC
can activate CD4+ T cells and
CD8+ T cells at the same time
with the absence of different
MHC class molecules. CD8+
cytotoxic T cells are activated by
MHC class I and co-stimulatory
signal while MHC class II with
also a co-stimulatory signal can
activate CD4+ T helper cells.
Activated T helper cells eventu-
ally either activate CD8+ T cells
or initiate a negative signal
against immune system based on
the absence of different environ-
mental cytokines
42 Tumor Biol. (2016) 37:39–45
cancer immune response by differentiating to T
H
1 cells, or
they can act for the regulation of this immune response. In
regulation process, T
H
17 cells have the capability to stimulate
and recruit T
reg
toward the tumor area. T
reg
cells can block or
inhibit the anti-cancer immune response by their specific an-
tigens that affect the CD8+ and its cytotoxic activity. As a
general behavior of T
H
17 cells, it has two different forms, as
effector and regulator, which are converted to those forms by
the composition of different types of cytokines affecting nat-
ural T
H
17 cells. T
H
17 cells gain a T
H
1/17 type of characteris-
tics in the presence of IL-1b, IL-6, and IL-12 that resulted in
the initiation of CTLs and in the regression of tumors, while in
the presence of TGF-β,T
H
17 cells transit into TH17/ Treg
cells and start to express Foxp3 in addition to RORγ-t that
causes the blockage of CD8+ T cells which feed the tumor
cells and keep their progression [42].
There have been many studies carried out on the role and the
functions of T
H
17 in different types of cancer including lympho-
mas. The level of T
H
17 cells was found very low in follicular
lymphoma (FL) compared to that in other non-Hodgkin lympho-
mas. It was also suggested that malignant B cells compress the
activation of T
H
17 cells and their differentiation that cause the
presence of a reduced number of T
H
17 in FL. The inhibitory
effects of B cells are also associated with the escalated T
reg
cells
in number and differentiation. As already mentioned before, the
increased level of T
reg
cells with a lack of T
H
17 differentiation
will result in the inhibition of immune response against the tu-
mor and its microenvironment in FL [6, 46].
T
reg
cells in tumor microenvironment
T
regs
are regulatory T cells that can be also named as suppres-
sive T cells. They have the both CD4 and CD25 receptors on
the surface, and those receptors can be used for identification
of those T
reg
cells in many research. In addition to those re-
ceptor set, there is a specific transcription factor for the T
reg
cells as FOXP3 which is an effective factor for the appropriate
function and proper development of those cells. Naive T cells
can be converted to regulatory T
reg
cells in the existence of
TGF-β and IL-6 cytokines by increasing the expression of
some specific transcriptional factors as Stat3, Gfi1, and ROR
and produce IL-17 and IL-10 without production of IFN-γ.
Besides, there is another molecule that is secreted by those
regulatory T
reg
molecules as adenosine, which can act as an
immunosuppressive molecule to prevent the anti-cancer im-
mune response. Human immune system involves T
reg
cells in
thymus, peripheral blood, lymph nodes, and spleen, and in
many cancer types, higher produced levels of T
reg
were de-
tected in breast, colon, lymphomas, lung, and melanoma. In
addition to vital roles of T
reg
, their presence and densities have
been shown as a prognostic indicator in cancer patients. For
instance, there are an increased number of T
reg
cells around the
ovarian cancer microenvironment and those highly existed
numbers of T
reg
cells affect the progression of cancer and
patient survival rate with poor prognosis. As ovarian cancer
does, malign melanoma or breast cancer patients with relapses
also have the increased amoun t of T
reg
compa red to non-
relapsed patients. This situation was also confirmed by the
studies in liver cancer patients with the same outcome [6,
42, 45].
Conclusion
Solid tumors in humans have their own specific microenvi-
ronment including inflammatory, stromal, and cancerous cells
within cancer stem cells. The poor progression of the disease
or the aggressiveness of the tumor is mostly related with its
niche. The factors involved the formation of that environment
or the initiator molecules mostly cytokines or chemokines that
are secreted from the different cell components which are
resident in this specific microenvironment. The different com-
pounds of tumor microenvironment include CAFs, epithelial
cells, cancerous cells, cancer stem cells, or mesenchymal stem
cells and immune cells such as lymphocytes (T cells, B cells),
DCs, macrophages, or NK cells. Although immune cells co-
operate with the immune response against foreign antigens,
tumor cells ha ve the capacity to escape from the immune
attacks through different mechanisms. Also, immune cells
could play roles on this escape mechanism, or they can pro-
mote the growth of the tumor because each of them could act
differently according to environmental conditions. As a major
part of the immune system, cell-mediated immunity within T
cells generates the immune response against the tumor anti-
gens. The tumor cells can mediate the T cell response by
secreting cytokines that promote the immunosuppressive en-
vironment. Specifically, T cell subsets (T
H
1, T
H
2, T
H
17, and
T
reg
) form the majority of T cell-mediated immune response
by the following: (i) T
H
1 cells are believed to be more effec-
tive compared to T
H
2 and favor the immune response and
CTL activity in order to make the tumor regress and shrink;
(ii) T
H
2 cells also support the CTL activity, but distinctly, they
also initiate B cell activity to enhance B cell-mediated immune
response; (iii) T
H
17 cells, the most studied T cell subtype in
tumor immunity, which are also known as having stem cell-
like plastic features, resulted in having contravariant effects
that are based on the type of cytokine presence and the tran-
scription factors; and (iv) T
regs
are the regulatory T cells which
prevent the CTL activity, and conversely to other T cell sub-
sets, they promote the tumor growth.
The failure against the immune cells/attack is basically
known as the biggest challenge in cancer treatment. Although
there are many studies that investigate the role of T cells in
tumors and its environmental pattern, it is still needed to illus-
trate other possible mechanism of tumor cells’ escape from the
immune system on the specific type of cancer since each type
Tumor Biol. (2016) 37:39–45 43