ANTICANCER RESEARCH 35: 311-318 (2015)
Presence of CD3-Positive T-Cells in Oral Premalignant
Leukoplakia Indicates Prevention of Cancer Transformation
JENNY ÖHMAN1, RAKEEBA MOWJOOD1, LENA LARSSON2, ANIKÓ KOVACS5,
BENGT MAGNUSSON1, GÖRAN KJELLER3, MATS JONTELL1 and BENGT HASSEUS1
Departments of 1Oral Medicine and Pathology, 2Periodontology,
3Oral
and Maxillofacial Surgery Institute of Odontology and 5Pathology, Institute of Biomedicine,
Sahlgrenska Academy, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden
Abstract. Aim: Leukoplakias (LPLs) are lesions in the oral
mucosa that have a potential to transform into oral squamous
cell carcinoma (OSCC). As the degree of immunosurveillance
may be important for this transformation to occur, the aim of
this study was to determine the presence of immune cells in
LPLs with dysplasia in relation to later development of OSCC.
Materials and Methods: Biopsies from 16 patients with
clinical diagnosis of LPL and histopathological diagnosis of
hyperkeratosis with dysplasia were immunostained with
antibodies to detect CD3+ T cells, CD1a+ LCs, Ki-67+ and
p53-expressing cells. Patients were divided into two groups:
LPL with dysplasia that transformed into OSCC (LPL-dys)
and that which did not (LPL-ca). Results: Quantitative
analyses showed significantly lower numbers of CD3+ T-cells
in LPL-ca than in LPL-dys. No significant differences were
detected when comparing LPL-dys and LPL-ca regarding
CD1a+, p53+ and Ki-67+ cells. Conclusion: The number of
CD3-expressing T-cells may be important for preventing
malignant transformation of LPL.
Leukoplakia (LPL) (Figure 1A) is a potentially premalignant
disorder in the oral mucosa (1). Approximately 3%-17% of
LPLs transform into oral squamous cell carcinoma (OSCC)
(Figure 1B) and the annual transformation rate is estimated
at approximately 1% (2, 3). The risk of malignant
transformation of LPL is difficult to predict. Several studies
have attempted to identify potential biomarkers that could
This article is freely accessible online.
Correspondence to: Jenny Öhman, LDS, Department of Oral
Medicine and Pathology, Institute of Odontology, Sahlgrenska
Academy, University of Gothenburg, SE-413 45, Göteborg, Sweden.
Tel: +46 317863166, e-mail: jenny.ohman@odontologi.gu.se
Key Words: Premalignant leukoplakia, oral cancer, immunosurveillance,
biomolecular markers.
0250-7005/2015 $2.00+.40
predict disease aggressiveness and clinical outcome.
However, no diagnostic or treatment modalities are currently
at hand that can prevent LPLs transforming into OSCC (4,
5). Hence, most clinicians arbitrarily regard the clinical
diagnosis, size and severity of cell dysplasia to be
proportional to the risk of malignant transformation.
During the last decades several studies have been carried
out addressing the importance of the immune system and
prognosis of cancer (6-8). The concept of cancer
immunoediting has resulted in a view of dynamic interaction
between the immune system and dysplastic cells/tumor cells,
with phases of elimination, equilibrium and escape (9). Thus,
in an early phase of cell dysplasia or early tumor cell
formation the immune system has the capacity to eliminate
cells with DNA damage that may result in, or already have
resulted in, cancer (10). Immunoediting is probably of
importance in the defence against malignant cells that may
occur in LPL. The importance of immune activation in the
defence against tumors in the head-neck region was observed
in the 1970s when tumor-infiltrating T-cells were found to
correlate to prognosis in OSCC (11). Since the initial reports
on the importance of T-cells in tumor progression, further
evidence has been provided regarding the role of T-cells and
other leukocytes in antitumoral defence and correlation to
treatment outcome (7, 12, 13).
Activation of T-cells demands interaction with other
leukocyte subsets. Dendritic cells (DCs) are effective
initiators of naive T-cells and can generate effector T-cells
with the capacity to eliminate tumor cells (14). DCs engulf,
process and present tumor-associated antigens (TAAs) to
naive or memory T-cells (15). Depending on the TAA-
presenting pathway, tumor-specific cytotoxic T-cells may be
generated (16). Dendritic Langerhans cells (LCs) are a subset
of DCs present in skin and mucosal linings, providing
immunosurveillance to these tissue compartments (15). In
the oral mucosa, an important role of LCs in evoking
antitumoral response may be expected, although no definite
proofs have been provided.
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 ANTICANCER RESEARCH 35: 311-318 (2015)
Figure 1. Leukoplakia on the right border of the tongue (A). The area was excised but 18 months later a squamous cell carcinoma appeared in the
region (B).
A number of clinical and experimental studies have
investigated T-cell response in established tumor diseases
(reviewed in (17)) but immune response in oral premalignant
lesions has not yet been extensively studied. The concept of
cancer immunoediting implicates that an immune response
may be mounted already in the premalignant phase, when
cells of the immune system recognize dysplastic cells.
In premalignant disorders, such as LPL, mechanisms affecting
both cell proliferation pathways and pathways involving growth
factors have been investigated in the pursuit of a reliable
biomarker foreseeing malignant transformation (18). Increase of
p53 expression in LPL has been reported to correlate with a
higher degree of malignant transformation in LPL (19).
Indices using the proliferation marker Ki-67 have also
been extensively studied and proposed as a predictor of
malignant transformation of LPL (19, 20). Altered
intracellular signalling results in alterations in cell surface
molecules and release of molecules recognized by cells of
the immune system (17). A linkage between molecular
markers like p53 and Ki-67 and immune response is likely
to exist, leading to interest in expression of these biomarkers
in the context of immune activation (21).
Our hypothesis is that recruitment of T-cells and DCs may
prevent malignant transformation in LPL with cell dysplasia.
Thus, the aim of this study was to compare the presence and
distribution of T-cells and dendritic Langerhans cells in a
group of LPL patients with no OSCC transformation and an
OSCC-transforming group.
Patients and Methods
Patients. Biopsy specimens from 11 patients (LPL-dys) with a
clinical diagnosis of LPL and a histopathological diagnosis of
hyperkeratosis with dysplasia and no record of malignant
312
transformation during follow-up were retrospectively retrieved from
the archives of the Department of Oral Medicine and Pathology,
University of Gothenburg. In parallel, 11 patients (LPL-ca) with a
clinical diagnosis of LPL and a histopathological diagnosis of
hyperkeratosis with dysplasia that transformed into OSCC, according
to patients’ records, were retrieved from the same archives, yielding
a total cohort of 22 patients. The biopsies were formalin-fixed and
paraffin-embedded specimens obtained between 1987 and 2003.
Biopsies were reviewed in a blind manner and independently by two
senior pathologists. One patient in the LPL-dys group and one
patient in the LPL-ca group – initially judged as hyperkeratosis with
dysplasia – were ascribed an early OSCC diagnosis. These patients
were excluded from further analysis, leaving 10 patients in each
group. Further on in this review, it was found that two patients in the
LPL-dys group showed signs of fungal infection within epithelium
and two patients in the LPL-ca group had received an OSCC
diagnosis, according to hospital records, within a month of primary
biopsy. Those patients were excluded from analysis. In total, 16
patients, 8 patients in each group, proceeded to final analysis. Patient
characteristics are described in Table I.
Follow-up periods for patients. In the LPL-dys group patients were
monitored for a median time period of 95 months (range=21–159)
without developing OSCC (Table I). Corresponding data for the
LPL-ca group revealed a median period of 62 months (range=7-192)
before transformation into OSCC occurred (Table I).
The Ethical Review Board at the Sahlgrenska Academy,
University of Gothenburg, approved the study and all patients signed
an informed consent before being included in the study.
Immunohistochemistry. Sections from paraffin-embedded biopsies
were retrieved and immunohistochemical staining was performed to
describe the presence and phenotype type of cells in tissue specimens.
Antibodies. Monoclonal antibodies raised against CD3 (LN10;
Novocastra, Newcastle, UK), CD1a (010; Dako A/S, Glostrup,
Denmark), p53 (D07; DAKO A/S) and Ki-67 (MIB-1; Dako A/S)
were used.
 Öhman et al: T-Cells in Oral Leukoplakia

Figure 2. CD3-positive T-cells in (A) leukoplakia without malignant transformation and (B) leukoplakia with malignant transformation. CD1a-
positive LCs in (C) leukoplakia without malignant transformation and (D) leukoplakia with malignant transformation. Ki67-positive cells in (E)
leukoplakia without malignant transformation and (F) leukoplakia with malignant transformation. p53-positive cells in (G) leukoplakia without
malignant transformation and (H) leukoplakia with malignant transformation. Positive cells stain brown. Magnification ×200.

Blocks of paraffin-embedded biopsies were cut into 4 μm- Antigen retrieval was carried out using TRIS ⁄EDTA pH 9.0 and
thick sections. The sections were then mounted on microwave treatment for 20 min. After cooling at room
electrostatically precharged slides (Superfrost Plus; Menzel- temperature (RT), the slides were rinsed in phosphate-buffered
Gläzer, Frankfurt, Germany), deparaffinized, and rehydrated. saline (PBS).

313
 ANTICANCER RESEARCH 35: 311-318 (2015)
Figure 3. CD3-positive T-cells in epithelium of (A) leukoplakia without
transformation (solid circles) and leukoplakia with malignant
transformation (open circles), and CD3-positive T-cells in connective
tissue of leukoplakia without malignant transformation (triangles) and
leukoplakia with malignant transformation (inverted triangles). (B)
CD1a-positive LCs in epithelium of leukoplakia without malignant
transformation (solid circles) and leukoplakia with malignant
transformation (open circles), and CD1a-positive LCs in connective
tissue of leukoplakia without malignant transformation (triangles) and
leukoplakia with malignant transformation (inverted triangles).
The sections were incubated with a primary antibody for 25 min
at RT. All subsequent washings were performed with the
ChemMate Buffer kit (K5006; Dako A⁄S). After blocking of
endogenous peroxidase using the ChemMate Peroxidase-Blocking
Solution (S 2023; Dako A⁄S), the sections were incubated with the
ChemMate DAKO EnVision Detection Kit, Peroxidase⁄DAB,
Rabbit⁄Mouse (K5007; Dako A⁄S) for 25 min at RT and developed
with DAB substrate. Counterstaining with ChemMate
Haematoxylin S2020 (Dako A⁄S) was followed by dehydration in
ethanol⁄xylene. Mountex (Histolab AB, Gothenburg, Sweden) was
used to permanently mount slides. Sections from tonsils served as
positive controls, while omission of primary antibodies served as
negative controls.
314
Figure 4. Ki67-positive cells in epithelium of (A) leukoplakia without
malignant transformation (solid circles) and leukoplakia with malignant
transformation (open circles), and p53-positive cells in epithelium of
(B) leukoplakia without malignant transformation (solid circles) and
leukoplakia with malignant transformation (open circles).
Quantitative analysis. Two compartments per biopsy, the
epithelium and the connective tissue, were selected for quantitative
analysis. Digitalized images of sections, where epithelium showed
dysplasia and corresponding connective tissue compartment, were
obtained with a light microscope (Leitz Wetzlar, Leica
Microsystems, Wetzlar, Germany) and digital camera (UC30;
Olympus, Microsystem, Norcross, GA, USA). One to six fields,
depending on biopsy quality, with epithelial dysplasia were
photographed at magnification ×63 (CD1a, p53, Ki-67, p53) or at
magnification ×100 (CD3). For all antibodies, sections were
analysed with computer software (CellSense; Olympus, Hamburg,
Germany). Positively stained nucleated cells were counted and
results were expressed as the number of positively stained cells ⁄
mm2. Cell counting was performed blinded by one observer, after
calibration with two other observers.
Statistical analysis. Analyses of differences between groups were
performed using the Mann–Whitney U-test, with the statistical
software SPSS v17 (SPSS Inc., Chicago, IL, USA). A p-value <0.05
was considered as a significant difference.
 Öhman et al: T-Cells in Oral Leukoplakia
Results
T-cells. T-cells were mainly seen in stratum basale and
stratum spinosum of the epithelium. In the connective tissue,
T cells formed a subepithelial infiltrate in close relation to
the epithelial basal cell layer (Figure 2A and 2B). The
number of CD3-positive cells per area unit was significantly
higher in the LPL-dys group compared to the LPL-ca group,
in both the epithelium and the connective tissue (Figure 3A;
p=0.016 and p=0.016, respectively)
Langerhans cells. CD1a-positive LCs were found
predominately in the epithelium but also in the connective
tissue, mostly scattered in the T cell infiltrate (Figure 2C and
2D). No significant differences between the two groups were
found regarding the number of LCs in either the epithelium
or connective tissue (Figure 3B; p=0.630 and p=0.248).
Ki-67. The proliferation marker Ki-67 was present on cells in
both epithelium and connective tissue in both LPL-dys and
LPL-ca, though in higher amounts in the epithelium than in the
connective tissue (Figure 2E and 2F). No statistically significant
difference was found between the number of proliferating cells
in LPL-dys and LPL-ca (Figure 4A; p=0.277).
p53. p53 was predominantly found in epithelium, while its
presence in connective tissue was rare (Figure 2G and 2H).
There was no significant difference in p53 expression when
comparing epithelium between the two groups (Figure 4B;
p=0.277).
Discussion
The main finding of this study is that a group of patients
with dysplastic LPL and no subsequent malignant
transformation had presence of significantly more T cells
compared to a group with LPL with dysplasia that later on
transformed into OSCC.
Tumor-infiltrating T-cells are important effector cells in
inhibiting tumor development. A “friend or foe” relation
exists as subsets of infiltrating T cells can guide disease
progression into different directions. CD8-positive and CD4-
positive T-cells without regulatory phenotype have been
shown to improve prognosis (22). On the other hand,
presence of CD4+CD25+ regulatory T cells is associated with
impaired disease control (23). Recently, myeloid-derived
suppressor cells and M2 macrophages have also been
ascribed a role in down-regulating an effective anti-tumoral
immune response (24).
The concept of immunoediting originally proposed by
Dunn et al., with phases of elimination, equilibrium and
escape (10), is well in line with the present state of
knowledge regarding immune activation and antitumoral
Table I. Patients’ characteristics.
LPL-dys LPL-ca
No. of patients (Female/Male) 8 (5/3) 8 (1/7)
Age in years (median; range) 71 (58-86) 68 (50-73)
Localization
Bucca 2 2
Gingiva 1
Lateral border of the tongue 3 5
Floor of the mouth 3
Degree of dysplasia
Mild 3 2
Moderate 4 4
Severe 1 1
Carcinoma in situ 1
Observation period in months
(median; range) 95 (21-159) 62 (7-192)
LPL-dys, Leukoplakia without malignant transformation; LPL-ca,
Leukoplakia with malignant transformation.
defence. Another important observation supporting the
influence of immunosurveillance in antitumoral defence is
that several studies report a dramatic increase in certain types
of tumors in solid organ–transplanted patients receiving
continuous immunosuppression (25, 26).
The bulk of knowledge accumulated during the last
decades has been almost exclusively gained in studies on
established tumors (13, 27-29). Less is known about immune
activation in premalignant disorders. In an earlier study we
reported that T-cells and dendritic Langerhans cells (LCs)
respond to cell dysplasia in LPLs (30), providing evidence
for immunosurveillance in this premalignant disorder.
In the present study we analyzed two groups of patients
with LPL with different clinical outcome, one group of
patients in which LPL developed into OSCC at the site of
initial lesions and one group where LPL did not transform into
OSCC during the observation period. In the group where the
patients did develop OSCC, significantly fewer CD3-positive
T-cells were registered, both in dysplastic epithelium and the
subepithelial connective tissue, in comparison with patients
that did not develop OSCC. Although the number of patients
analysed in this study is limited, a difference in the presence
of T-cells between non-OSCC-transforming and OSCC-
transforming patients with LPL was registered. This finding
lends further support to the immunosurveillance hypothesis,
although we have not characterized the T-cell subsets. So far,
most studies have emphasized the importance of presence of
CD8-positive cytotoxic T-cells in antitumoral defence but in a
recent study by Badoual (31) the presence of activated CD4-
positive T cells was found to have an influence on patients’
survival in head and neck tumors. Composition of the T cell
infiltrate and OSCC transformation needs to be addressed in
a prospective manner.
315
 ANTICANCER RESEARCH 35: 311-318 (2015)
DCs are important effector cells in antitumoral defence
(32). The LC subset has been investigated less. In an earlier
report from our group comparing LPL with and without
dysplasia, LCs were found to be more numerous in the
dysplasia group, indicating an ongoing immune response
(30). In this study, where all patients with LPL had
dysplastic changes in biopsy specimens, no significant
difference could be seen between the OSCC-transforming
and non-OSCC-transforming groups. This result does not
exclude the importance of DCs in the immunosurveillance
process in LPL. Other subsets of DCs, not investigated in the
present study, such as plasmocytoid DCs, possess a potent
antitumoral capacity (33) and may be involved in
orchestrating the antitumoral immune response in LPL.
In our patient cohort gender distribution differed between
the groups. There was a dominance of men in the LPL-ca
group, while women dominated in the LPL-dys group. In a
study by Ho et al. no gender difference in hazard ratios for
OSCC transformation from LPL with dysplasia between
males and females could be registered (34). However, gender
differences in environmental factors, such as smoking, may
influence the outcome. The present patients’ material is
relatively small to interpret the influence of gender on the
results but it is an issue that should be addressed
prospectively.
An increased cell proliferation is associated with worse
prognosis amongst patients with head and neck tumors (35).
The proliferation marker Ki-67 has been used for decades in
clinical and scientific settings. In oral leukoplakias, Vered
and co-workers have presented evidence for a correlation
with degree of dysplasia, malignant transformation and Ki-
67 expression (19). Another group has reported a correlation
between degree of dysplasia and Ki-67 expression (20). In
contrast, Torres-Rendon et al. could not detect any
correlation between Ki-67 expression and degree of
dysplasia, although the study showed correlation when a co-
labelling index with maspin was applied (36). In our patient
groups no significant correlation was detected, which
supports the findings by the aforementioned study.
In oral premalignant disorders, the expression of p53-
positive cells in the suprabasal layers of the epithelium has
been suggested as an indicator for malignant transformation
(37). In a study by Angiero et al., a high expression of p53
was seen in epithelium with increasing dysplasia (38). In
another study, an increased epithelial expression of p53 in
OSCC was observed in comparison to normal mucosa. This
study did not show any difference in p53 expression in
epithelium between patients that developed OSCC from
leukoplakia and patients who did not. However, the
presence of p53 molecules in LPL epithelium reinforces the
existence of an ongoing abnormal process, demanding
DNA repair in accordance with what Hanahan and
Weinberg propose (39).
316
In conclusion, the finding of the present study, increased
number of T-cells in non-OSCC-transforming LPL compared
to OSCC-transforming LPL, lends further to support the
importance of an immunomediated antitumoral defence
system. The findings should be further investigated in a
prospective manner.
Conflicts of Interest
The Authors declare no conflicts of interest.
Acknowledgements
This study was supported by the Agreement for Doctoral Education,
Region Västra Götaland, Sweden, the Assar Gabrielsson Foundation,
the Swedish Dental Society, and the Gothenburg Dental Society. The
authors are obliged to Ms. Christina Eklund, BSc and Ms. Marie
Svensson for valuable assistance in laboratory procedures.
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Received August 28, 2014
Revised September 9, 2014
Accepted September 15, 2014
317