1424-9634Academy of Cancer Immunology
Cancer Immun
Cancer Immunity (26 June 2007) Vol. 7, p. 10
Copyright © 2007 by Padmanee Sharma
070610
Review
Focus on TILs: Prognostic significance of tumor
infiltrating lymphocytes in human bladder cancer
Chrysoula I. Liakou1, Sowmita Narayanan1, Derek Ng Tang1, Christopher J. Logothetis1 and Padmanee Sharma1,2
1Department of Genitourinary Medical Oncology, University of Texas, M. D. Anderson Cancer Center, Houston, TX, USA
2Department of Immunology, University of Texas, M. D. Anderson Cancer Center, Houston, TX, USA
The idea of generating cytotoxic T-lymphocytes that have anti-tumor
perivesical fat is designated as pT3. Disease beyond the bladder
activity has been the focus of many clinical trials aimed at delivering
and extending to nearby organs or structures is designated as
effective immunotherapy to cancer patients. We have gained insight
pT4 (Figure 1A). Disease that has spread to distant sites from
into the human immune system in cancer patients as a result of these
the bladder is labeled as metastatic.
numerous clinical investigations. It is now clear that although
In the setting of non-muscle invasive disease, intravesical
various vaccination methods are capable of inducing tumor antigen-
bacillus Calmette-Guérin (BCG) is pivotal as an immunological
specific T-cells in the circulating blood, these immunological agent in the treatment of early TCC and leads to a cure rate of
responses are infrequently correlated with clinical responses. approximately 90% in select patients, such as those with unifocal
Therefore, it appears that priming of a T-cell response is not
and pathological T1 lesions. Intravesical BCG has been used to
sufficient for tumor regression and other avenues, downstream of the
treat superficial TCC for more than 20 years; randomized trials
priming phase, need to be investigated. Mechanisms of immune
have shown that BCG results in lower recurrence rates and
evasion at the effector phase of the anti-tumor phase are currently
significantly superior survival rates (1). Although the
under investigation, with an increasing focus on the tumor mechanism of action of BCG is poorly understood, scientific
microenvironment. There is evidence indicating that multiple evidence continues to implicate an immunological mechanism.
variables may contribute to immune escape, including: regulatory
BCG plays a significant role in the maturation of dendritic cells
cells; inhibitory ligands on tumor cells, such as PD-L1 and B7x;
(DCs) by signaling through different Toll-like receptors, as
soluble factors such as TGF-β and IL-10; and nutrient-catabolizing
indicated by its upregulation of the DC maturation marker
enzymes, such as indoleamine-2,3-dioxygenase (IDO). In addition,
CD83 (2) and secretion of inflammatory cytokines such as IL-
there are ongoing efforts to assess the presence and function of
12, IFN-γ, and TNF-α. A variety of cytokines has been detected
effector cells within the tumor microenvironment. Tumor in the urine of patients treated with intravesical BCG, and BCG
infiltrating lymphocytes (TILs) have been observed in patients with
causes an influx of granulocytes and mononuclear cells into the
melanoma, colon cancer, and ovarian cancer. TILs in these patients
bladder wall (3-10). Although the significance of these
have been associated with favorable clinical outcomes. In the clinical
infiltrating cells remains controversial, there are ongoing studies
setting of bladder cancer, as compared to melanoma, there is limited
to characterize these cells and assess their functional status.
data regarding TILs. This review will focus on immunological
responses to bladder cancer and ongoing studies to identify factors
that are amenable to therapeutic manipulation.
Immunological alterations that occur with the
development of bladder cancer
Apart from the physiological changes in and around the
Keywords: human, bladder cancer, tumor infiltrating bladder as a result of tumor development, there are several
lymphocytes, prognosis
notable immunological changes that occur simultaneously.
Changes may be phenotypic in nature, such as the loss or
addition of certain molecules on the cell surface of the urothelial
Bladder cancer
cells, or changes may be related to the functionality of certain
Bladder cancer, the majority of which are diagnosed molecules.
pathologically as transitional cell carcinoma (TCC) or urothelial
Blood group antigens, major histocompatibility complex
carcinoma (UC), is the only solid tumor other than melanoma
(MHC) antigens, and other cellular adhesion molecules which
for which immunotherapy confers a survival benefit. The are expressed on the cell surface of normal cells tend to have
tumors of the bladder can be classified depending on their depth
variable expression on bladder cancer cells. For example,
of invasion. The bladder lining consists of a mucous layer of decreased expression and incomplete biosynthesis of certain
surface cells, called transitional epithelial cells or the urothelium
proteins in the family of blood group antigens have been noted
that expand and deflate depending on the volume of urine (11-12). It has also been observed that the loss of blood group
present inside the bladder. Disease that affects only the antigens increases irreversibly with tumor progression. The class
urothelial lining can be papillary and designated as pTa disease.
I human leukocyte antigen (HLA) in humans, otherwise known
Underneath the urothelium is a thin layer of connective tissue,
as MHC class I antigen, is normally expressed on the urothelial
also called the lamina propria, and tumor in this area is cell surface; however, in urothelial malignancies, it has been
designated as pT1 disease. The next layer is a wider zone of observed that there is a loss of HLA class A, B and C expression
muscle tissue called the muscularis propria, with disease (13-16). Such a loss of MHC class I antigen expression also
involvement designated as pT2. Beyond this muscular zone,
directly correlates with tumor progression. Some other
another layer of fatty connective tissue separates the bladder molecules that play a role in immuno-oncology and cellular
from other nearby organs and disease extending to this adhesion events also appear to be diminished in their expression
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Cancer Immunity (26 June 2007) Vol. 7, p. 10
Figure 1
Bladder cancer and TILs. (A) Urothelial carcinomas can be classified as pTa (papillary), pT1 (lamina propria invasion), pT2 (muscle invasive), pT3 (invasion to peri-
vesical fat), and pT4 (locally advanced). (B) Interaction of FasL on tumor cells and Fas-positive T-lymphocytes leads to elimination of Fas-positive TILs, which appears to
be a caspase-mediated event.
in the initial stages of bladder malignancies. Molecules such as
Tumor infiltrating lymphocytes in the tumor
CD44 and ICAM-1, which normally promote the adhesion and
microenvironment
activation of T-lymphocytes, seem to have decreased expression
Tumor infiltrating lymphocytes (TILs) are lymphocytes of the
on bladder cancer cells (17-18).
host immune system that have been observed within tumor
Furthermore, certain subpopulations of circulating immune sites; presumably they migrate to the tumor site in order to
cells appear to be associated with clinical outcome in UC combat the growing malignant cells. They are normally
patients. Innate immune cells, known as natural killer (NK) activated T cells, natural killer cells and non-T or non-B
cells, obtained from circulating peripheral blood mononuclear
lymphocytes. These lymphocytes can be physically
cells of bladder cancer patients were studied in 67 patients and
characterized by cluster differentiation and certain surface-
29 healthy donors. A decreased NK cell activity in TCC patients
antigen groupings. However, the phenotypic characteristics and
was observed as compared to healthy controls and furthermore,
the T-cell populations in cultured TILs can be affected by the
it was noted that disease recurrence was associated with components of culturing media as demonstrated by Haas et al.
decreased NK cell activity (19).
(21) and Housseau et al. (22). In the study by Haas et al. (21), the
Another factor which appears to impact the immunological isolation and expansion of human TILs from urological
response to bladder cancer is cellular architecture. In one study
malignancies, including testicular, bladder, and prostate cancer,
(20), the impact of physical changes in cellular architecture on
were examined. The initial TIL population was mainly
autologous T-lymphocyte activation was examined. Two comprised of CD3+ T-cells, with subpopulations of CD4+ and
autologous bladder carcinoma cell lines were used as targets for
CD8+ T-cells. The authors observed that over time, the ratio of
T-lymphocytes. In an effort to compare the effect of cell CD4+ and CD8+ subpopulations varied as a consequence of
architecture of these targets on the overall cytokine production
culture conditions. In the study by Housseau et al. (22), human
levels, the cell lines were grown with varying cellular geometry
TILs from primary urothelial carcinomas were characterized.
including a two-dimensional monolayer and a three-
The cytolytic properties of these TILs were examined by the
dimensional spheroid. Interestingly, it was observed that there
establishment of short-term autologous tumor cell lines for
was a reduction in cytokine production by T-cells after obtaining neoplastic targets with minimal phenotype
interaction with the three-dimensional structure of tumor cells
modifications in comparison with fresh tumor cells; five pairs of
as compared to the two-dimensional structure of tumor cells. autologous TIL/tumor cell pairs were examined. Four of the five
The data implied that information obtained from a two-
TIL cultures manifested lysis against their autologous
dimensional structure of the cells in an in vitro study may not be
counterparts and three of these four cytotoxic TIL lines
comparable to in vivo occurrences as mimicked by the three-
demonstrated MHC class I-dependent cytotoxicity, as
dimensional tumor microenvironment. Cellular architecture established by blocking experiments with anti-HLA class I mAb
also appears to play a role in the immune response generated in
W6.32. One of these three TIL lines, which demonstrated high
the tumor microenvironment.
levels of cytotoxicity, was further examined and was found to
have numerous CD8+ T-cells. The depletion of CD4+ cells from
this culture indicated that CD8+ MHC class I CTLs were the
predominant effectors.
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Liakou et al.
Even though these studies demonstrated that there are effector
compromising their efforts in anti-tumor cytotoxicity.
cells in urothelial carcinomas that are capable of specific Furthermore, it has been found that the enzyme IDO is
cytotoxic activity against tumor cells, the fact remains that these
produced by tumor cells in order to resist attacks by the host
effector cells are incapable of suppressing tumor growth in vivo.
immune system (38) and thus weaken or even nullify the effects
Some studies have proposed activation-induced cell death of potential immunosurveillance mechanisms.
(AICD) to be a major cause of death of TILs, thus explaining
Furthermore, it appears that a mechanism of "cancer
their inability to control tumor growth (23-25). Other studies
immunoediting" may be responsible for the development of
have proposed that cancers can become "immune privileged" tumors that are resistant to immune-mediated events.
sites by expressing Fas-ligand (26-28). Fas-ligand (FasL) is a cell
Shankaran et al. (39) demonstrated that the immune system
surface protein of the tumor necrosis factor family that induces
may promote the emergence of primary tumors with reduced
apoptosis on Fas-bearing cells when FasL binds to Fas. Fas-
immunogenicity that are capable of escaping immune
mediated apoptosis is dependent on the activation of different
recognition and destruction. The hypothesis of cancer
members of a family of cysteinylaspartate proteases called immunosurveillance, which states that sentinel thymus-
caspases, including caspase-8, -9, and -3, which are responsible
dependent cells of the body constantly survey host tissues for
for both the initiation of the apoptotic cascade and the execution
nascently transformed cells, has been demonstrated in several
of the cell damage. Interaction of FasL with Fas+ TILs has been
studies (40-42). However, since immunosurveillance represents
demonstrated to lead to cell death (29). Therefore, expression of
only one dimension of the complex relationship between the
FasL by tumor cells may provide a mechanism by which cancer
immune system and cancer, the hypothesis of cancer
cells escape eradication by TILs (Figure 1B).
immunoediting was proposed to encompass the various
In a recent study by Chopin et al. (30), FasL expression was
interactions, including elimination, equilibrium, and escape,
observed in 45% (n = 45) of TCC samples, while expression of
that occur between the host immune system and developing
FasL was not observed in normal urothelium (n = 20). A cancer cells. In the elimination phase, the immune system is able
correlation existed between FasL expression and high tumor to eradicate developing tumor cells; however, as the immune
grade and stage (13% in superficial Ta-T1 versus 81% in invasive
system continues to exert pressure on the tumor cells, escape
T2-T4; P < 0.0001). Two primary bladder TCC cell lines, variants occur and are able to persist in a state of equilibrium,
established from two FasL-positive invasive bladder TCC whereby the immune system keeps further development of these
tissues, were shown to specifically mediate FasL cell death in two
cells at a minimum until finally, the escape phase occurs when
conventional Fas-sensitive T lymphocyte targets. Further the cancer cells have accrued sufficient mutations that enable
analysis of one of these cultures demonstrated its ability to evasion of the immune system (42).
induce FAS-mediated killing of autologous T-lymphocytes in
Therefore, there are many mechanisms which appear to
vitro. Fas-mediated apoptosis of IFN-γ-producing CD8+ TILs
contribute to the inefficiency of TILs in their ability to eradicate
was evident by the detection of activated caspases -8, -9, and -3
tumor cells. Deeths et al. (43) proposed that certain tumor cell
expression on these cells, which were found in close association
mechanisms, such as activation-induced non-responsiveness
with FasL-expressing TCC cells in situ. In short, these results
(AINR), may possibly induce CD8+ TILs death, thus
suggest that TCC-expressed FasL may induce apoptosis of anti-
jeopardizing the cytotoxic abilities and functions of the host
tumor T-lymphocytes in vivo and may provide new insights into
immune system. Other mechanisms, such as down regulation of
the mechanisms that allow for the suppression of TIL HLA class I molecules, loss of co-stimulatory molecules, and
immunological function.
removal or blocking of tumor antigens by tumor cells also result
In addition, signaling defects in TILs have also been in immune escape by tumor cells. Contrastingly, some
implicated in the dysfunction of lymphocytes at the tumor site.
investigators have also explored the possible inherent reasons
These include loss of signal-transducing zeta (ζ) chain (31) or
for the inhibition or the inability of CD8+ TILs to counter the
reduction in the epsilon chain of p56, Zap70 and p59 expression
antagonistic tumor cells. Two mechanisms have been proposed:
(32-33). In some experiments, the lost ζ chain was seen to be
a defect in the cytolytic pathways or an overexpression of
reversible after treatment with IL-2 (34). Another signaling inhibitory molecules. Recent studies by Sheu et al. (44) illustrate
mechanism that emerged quite recently and which could that the down-regulation of perforin completely blocks the
potentiate the down regulation of TIL proliferation and cytotoxic mechanisms of TILs. Additionally, they also found
activation is an alteration in the signaling pathways of IL-2/IL2R
that inhibitory NK receptors such as CD94/NKG2A can be up-
(35). It has also been observed that cancer-derived matrix regulated on TILs by cytokines such as IL-15 and TGF-β which
metalloproteinases (MMP) play an important role in cleaving
are derived from cancer cells. This can be a further contributing
IL2Rα chain, thus resulting in host immunosuppression, tumor
factor for the inertness of cytotoxic TILs in their response
metastases, and lymphovascular invasion by interfering with the
towards tumor cells. All of these mechanisms can be seen as
signaling pathways of IL-2 (36).
potential targets for novel immunotherapy agents that are aimed
Other studies indicate that the enzyme indoleamine-2,3-
at overcoming the suppressive and regulatory factors within the
dioxygenase (IDO) is responsible for creating an tumor microenvironment.
immunosuppressive environment. IDO, an enzyme classically
known for its role in the tryptophan degradation pathway, has
recently emerged as an important immunomodulator of T-cell
TILs as a prognostic factor in bladder cancer
function and inducer of tolerance. The induced expression of
An early study by Mostofi et al. (45) reported a favorable
IDO by dendritic cells may suppress T-cell responses and prognosis with higher number of TILs present in TCC. Later, a
promote tolerance either through direct effects on T cells prolonged recurrence-free survival rate was correlated with an
(mediated by tryptophan depletion or tryptophan metabolites)
increased number of T-zone histiocytes in TCC indicating a
or through effects of IDO on the dendritic cell. Friberg et al. (37)
competent host immune system as a favorable factor (46).
observed that the enzyme IDO is responsible for metabolizing
According to another study (47, 48), denser TILs were
tryptophan found on antigen presenting cells, thus associated with invasive (pT3-T4) TCC tumors as opposed to
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Cancer Immunity (26 June 2007) Vol. 7, p. 10
superficial papillary tumors. It appears that a higher prevalence
occur as a result of mutations within tumor cells eventually
of TILs is associated with a favorable response, even in the create an immunosuppressive tumor microenvironment that
setting of a more invasive disease.
prevents tumor eradication by TILs. Nevertheless, new findings
In another study by Tsujihashi et al. (49), a comparison of the
and research on TILs and the tumor microenvironment are
functional activities of TILs and peripheral blood lymphocytes
ongoing in efforts to reverse the multitude of
(PBLs) from 22 bladder cancer patients led to the conclusion immunosuppressive mechanisms.
that a higher number of TILs was associated with better clinical
The rational development of immunotherapy applicable for
outcome and fewer occurrences of tumor metastases. TILs and
patients with solid tumors, analogous to that used for
PBLs were isolated from the patients and used against a natural
molecularly targeted therapy, is possible. Improvements in the
killer (NK) myeloid leukemic line, myeloid K562, a fresh understanding of immune regulation in the context of cancer, as
bladder tumor, and a cultured bladder tumor, HT1197, as their
well as novel agents that are able to target specific immune
targets in vitro. The amount of lymphocytes in TILs and PBLs
regulatory pathways, and evolving methodology to characterize
was measured by flow cytometry and showed a predominantly
human cancer at the cellular and molecular level will result in
higher cell population of T-cells present in both PBLs and TILs.
more informative clinical studies. The knowledge gained
A 51Cr release cytotoxicity assay revealed that there was a through the proposed integration of tumor biology with
spontaneous response to the NK target cells by the PBLs which
immunology will be the foundation for the effective application
was of 23.4%, compared to the response by the TILs which was
of immunotherapy to the treatment of solid tumors. Our
of 3.5%. But when the TILs and PBLs were cultured with an ongoing studies in bladder cancer include utilization of a novel
immunomodulating cytokine, IL-2, it was noted that immune
anti-CTLA4 monoclonal antibody aimed at releasing the
responses by both the PBLs and TILs were enhanced. However,
inhibitory mechanisms on T-cells so as to enhance T-cell activity
interestingly, there was a tumor-specific response by TILs which
against tumor cells. We are currently enrolling bladder cancer
was not observed for the PBLs. The cytotoxic response of IL-2-
patients onto a phase I neoadjuvant clinical trial with anti-
treated TILs was higher against autologous bladder cancer CTLA4 and will conduct in-depth immunological studies on the
tumors than against the artificially cultured tumor tissue, obtained tumor tissues to characterize the various TIL
HT1197. Therefore the presence of IL-2, a lymphokine known
populations and their function as compared to TILs obtained
to be released from helper T-cells for the generation of cytotoxic
from untreated tissues. These types of studies will continue to
T-cells, boosted the TIL cytotoxic response to the tumor tissues
provide valuable information regarding the significance of
in vitro (49-50). These data continue to support the concept that
various subpopulations of TILs and therapeutic agents that will
TILs are capable of effective immunity against tumor cells when
enhance anti-tumor responses by TILs in bladder cancer
the appropriate immunomodulatory agents are present.
patients.
In another study by Lipponen et al. (51), tumor tissues from
514 patients with TCC were analyzed for a correlation between
TILs, recurrence-free survival and metastases. Biopsy Abbreviations
specimens from tumor tissues were analyzed by histological BCG, bacillus Calmette-Guérin; IDO, indoleamine-2,3-dioxy-
staining in order to categorize the tumors as papillary or genase; TCC, transitional cell carcinoma; UC, urothelial carci-
nodular. The quantification of TILs was categorized as: weak or
noma
absent; moderately populated; or densely populated. In pTa-pT1
staged, papillary grade tumors, a higher density of TILs
indicated an unfavorable prognosis, and these patients were References
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Document Outline

• Focus on TILs: Prognostic significance of tumor infiltrating lymphocytes in human bladder cancer
  • Bladder cancer
  • Immunological alterations that occur with the development of bladder cancer
  • Tumor infiltrating lymphocytes in the tumor microenvironment
  • TILs as a prognostic factor in bladder cancer
  • Conclusions and future directions
  • Abbreviations
  • References
  • Contact

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