Clinicopathologic Evaluation of CD80, CD86, and PD-L1 Expressions with Immunohistochemical Methods in Malignant Melanoma Patients
Esra COBANKENT AYTEKIN1, Betul UNAL2, Cumhur Ibrahim BASSORGUN2, Ozlenen OZKAN3
1Department of Pathology, Konya Numune Hospital, KONYA, TURKEY
2Department of Pathology, Akdeniz University, Faculty of Medicine, ANTALYA, TURKEY
3Department of Plastic and Reconstructive Surgery, Akdeniz University, Faculty of Medicine, ANTALYA, TURKEY
Keywords: CD80, CD86, Immunopathology, Melanoma, PD-L1
Diagnostic and prognostic biomarkers for malignant melanoma are crucial for treatment and for developing targeted therapies.
Malignant melanoma is a highly immunogenic tumor, and its regression, treatment, and prognostic evaluation are directly related to escape from
immune destruction. Therefore, we aimed to determine the expression levels of CD80, CD86, and PD -L1 in malignant melanoma tissue samples
by immunohistochemistry and to investigate the possible relationship between these proteins and the clinicopathological features in this study.
Material and Methods: Hematoxylin and eosin staining and immunohistochemical staining for CD80, CD86, and PD-L1 were evaluated for
clinical data, survival, prognosis, tumor location, malignant melanoma subtypes, tumor size, and prognostic findings.
Results: Higher survival rates were observed in patients with lower PD-L1 staining scores in the tumor. The 5-year survival was higher in patients
with CD80-positive and CD86-positive biopsies. Mortality was lower in superficial spreading melanoma and Lentigo maligna melanoma
types, whereas staining positivity of CD80 and CD86 was higher. Furthermore, a relationship between clinical stage and Breslow thickness
(<2mm/≥2mm), tumor ulceration, lymph node metastasis, and CD80 and CD86 expression was also identified.
Conclusion: Our findings suggest that PD-L1, CD80, and CD86 expression are essential in malignant melanoma and could be used as prognostic
Malignant melanoma (MM) is a tumor with high immunogenicity
due to tumor antigens1
. Because of this feature
of MM, treatment protocols are centered on immunotherapeutic
approaches, which include targets such as induction
of anti-tumor immune responses, modulation of tumortargeted
immune reactions, and inhibition of immune control
Like many other tumors, tumor cells in MM inactivate the
immune system through various escape mechanisms2.
The change in co-stimulatory receptors on dendritic cells
is one of these escape mechanisms. The two-signal model
proposes that activation of naive T cells requires both stimulation
of T cell receptor (TCR) by major histocompatibility
complex (MHC)-peptide molecules (signal 1) and co-stimulation via co-stimulatory receptors and their corresponding
ligands on antigen-presenting cells (APCs) (signal
2). In this pathway, the tumor reduces (downregulates)
the number of activating co-stimulatory receptors (CD28,
CD40, OX40, CD137) or increases (upregulates) the number
of inhibitory surface receptors (LAG-3, CTLA4, B7-H3,
PD-1) in dendritic cells1,3.
Programmed cell death receptor-1 (PD-1), a co-inhibitor,
is expressed in T, B, and some myeloid cells. PD-L1 and
PD-L2 are ligands expressed by various cells, including
tumor cells, monocyte-derived myeloid dendritic cells,
epithelial cells, and T and B cells3-5. PD-L1/PD-1 interactions
inhibit T cell growth and cytokine production. Furthermore,
tumor cell PD-L1 can inhibit or cause apoptosis
of tumor-specific T cells4.
Immune T cells detect and respond to antigens presented
by MHC on antigen-presenting cells and tumor cells. Coactivator
signals are required for full activation of the T cell
response. T-cell activity is inhibited when B7 of antigenpresenting
cells (APC) binds to CTLA-4 of T-cells. B7
proteins are classified into two types: B7-1, also known as
CD80, and B7-2, also known as CD86. CD28 and CTLA-4
(CD152) proteins can interact with B7-1 and B7-26.
Recent research has revealed that CD80 and CD86 have
both immunological7,8 and non-immunological functions
(9,10) and that CTLA-4 can act as an inhibitor independently
of CD80 and CD86 (11). In addition, CD80 and
CD86 are also involved in anti-tumor immunity12-14.
Although studies have shown the expression of CD80 and
CD86 in tumor cells, the related studies are limited, and
their relationship with prognosis is unclear2. As a result,
the goal of this study was to look at the expression rates
of CD80, CD86, and PD-L1 on paraffin sections from 80
malignant melanoma cases using immunohistochemistry,
as well as to evaluate the possible correlation between
these proteins and clinical features like the stage, prognosis,
and survival, in order to see if these proteins can be used
as prognostic markers and to shed light on new treatment
Between 2005 and 2015, 80 patients diagnosed with MM
were included in this study. The samples, of which 2 were
incisional biopsies and 75 were excisional biopsies, were
fixed in 10% buffered formalin, embedded in paraffin, cut
into 4 mm thick sections, and stained with hematoxylin
and eosin. A total of 3 consultation paraffin blocks were
cut into 4 mm thick sections and stained with hematoxylin
and eosin. In the presence of more than one block, we
chose the block with the highest tumor ratio. In addition,
demographic data such as age, gender, and clinical findings
were retrieved from the files using the hospital automation
Four-micrometer-thick sections were cut from each
patient’s paraffin block. One of these sections was stained
with hematoxylin and eosin (HE), and the others were
immunohistochemically stained with antibodies against
CD80 (Anti-CD80 antibody [2A2], 1/800, Abcam, UK),
CD86 (Anti-CD86 antibody [EP1158Y], 1/800, Abcam,
UK), and PD-L1 (Anti-PD-L1 antibody [ABM4E54],
1/1000, Abcam, UK). Two pathologists evaluated the
stained sections. (CIB, ECA) We included a third pathologist in the study if the two pathologists could not reach a
consensus about the diagnosis.
In this study, we developed a method of evaluating and
scoring inspired by studies by Flörcken et al2. Positive
staining for CD80 and CD86 in tumor cells was characterized
by cytoplasmic and membranous staining2. PD-L1
was considered as positive when complete or partial linear
membranous staining and nuclear staining were observed
in tumor cells and tumor-infiltrated lymphocytes. Tonsillar
tissue sections were positive controls for all PD-L1,
CD80, and CD86 immunostainings2,15,16.
We scored the staining intensity for CD80, CD86, and
PD-L1. A score of 0 indicated no staining, while a score of
+1 indicated weak staining. A score of +2 was for medium
staining, and a score of +3 was given for intense staining.
≤10% positive staining of tumor cells was evaluated as 1
point, 10.1-50% positive staining as 2 points, and 50.1-
100% positive staining as 3 points. The staining value was
calculated by adding the staining percentage and intensity
values. The patients were divided into groups based on
their staining scores: those with a score of 0-4 and those
with 5-6. Cases in the study were also classified as positive
or negative for CD80 and CD86. The immunohistochemical
staining results were evaluated based solely on the presence
or absence of lymphocytic infiltration; however, no
assessments were made regarding whether the infiltration
was brisk or non-brisk.
Descriptive findings were presented as number and
percentage distributions for categorical variables, and
mean±standard deviation for continuous variables.
The Pearson Chi-square test was used to compare categorical
variables. For survival analysis, survival probabilities
were first estimated with the Kaplan-Meier method and a
log-rank test was performed to see if there was a difference
between variable levels in terms of survival probabilities.
The University Institute of Health Sciences, Medical Statistics
Consultancy Center used SPSS Package Program
v20 to conduct the statistical analysis for the study (IBM,
USA). Statistical significance was defined as p values less
The median age of the patients was 57 years (range: 25-89
years). Among the study group, the death rate was 46.8%
(n=22) in males, and 33.3% (n=11) in females, with no statistically significant difference between the two genders
(p=0.256). Based on the World Health Organization’s
classification of malignant melanoma, we identified 18
melanocytic tumors in intermittently sun-exposed skin
(Superficial spreading melanoma), six melanocytic tumors
in chronically sun-exposed skin (5 Lentigo maligna melanoma
+1 desmoplastic melanoma), 20 melanoma arising
at sun-shielded sites or without known etiological associations
with UV radiation exposure (19 acral lentiginous
melanoma and 1 balloon cell melanoma), and 36 nodular
The patients in the study had a median tumor size of 1.78
cm in diameter (min: 0.2 cm, max: 7.6 cm), with 12.5%
(n=10) having tumors smaller than or equal to 0.6 cm in
diameter and 87.5% (n=70) having tumors larger than
0.6 cm in diameter. On the other hand, the patients in
the study were divided into two groups based on reticular
dermis invasion, Clark I-II, and Clark III-IV-V, with the
Clark level I-II group accounting for 11.3 % of all patients
(n=9). The Clark level III-IV-V group accounted for 88.7%
(n=71). The mean Breslow thickness in all patients was
3.6.±3.24 mm: 37.5% (n=30) having a Breslow thickness
of <2 mm, and 62.5% (n=50) having a Breslow thickness
of ≥2 mm. Ulceration was found in 37.5 % of the patients
(n=30). Regarding growth phases, 7.5 % of patients (n=6)
showed only the radial growth phase, while 92.5 % (n=74)
showed both the vertical/radial and vertical growth phases.
Lymphocytic infiltration was found in 58.8% (n=47) of
the patient samples examined. There was evidence of neurotropism
in 23.8% of the cases (n=19). Regression was seen
in 18.7% (n=15) of the patients, while lymph node metastasis
was seen in 20% (n=16). 51.2 % (n=41) of the patients
in the study were in Stages 1-2, while 48.8 % (n=39) were in
Stages 3-4. The patients’ mean follow-up period was 57.72
± 30.32 months (min: 0; max: 121 months). The mortality
rate was 41.3% (n=33) during the follow-up period. Superficial
spreading melanoma and lentigo maligna melanoma
types, patients with Breslow thickness less than 2mm, the
group without tumor ulceration, those with only radial
growth phase, and clinical stage 1-2 all had lower mortality.
Clinicopathological Correlations with
Expression of PD-L1
As previously described, PD-L1 staining was assessed on
tumor cells and tumor-infiltrating lymphocytes2. Tumor
cells had a low staining score (28/80) in 35% of the patients
and a high staining score (52/80) in 65% of the patients,
while tumor-infiltrating lymphocytes (TIL) had a low staining score (34/80) in 42.5% of the patients and a high
staining score (46/80) in 57.5% of the patients. Figure 1A-D
shows examples of low and high staining scores in tumors
and TIL. PD-L1 expression and staining score were high in
clinical stage 3-4 cases.
Click Here to Zoom
|Figure 1: A) Strong membranous and nuclear immunohistochemical PD-L1 staining in tumor cells (PD-L1x400), B) Strong
immunohistochemical PD-L1 staining in lymphocytes, negative staining in spindle tumor cells (x200), C) Membranous and
nuclear immunohistochemical PD-L1 staining in tumor cells, negative staining in lymphocytes (PD-L1x400), D) Weak nuclear
immunohistochemical PD-L1 staining in tumor cells, strong positive staining in lymphocytes (PD-L1x400).
Patients with low PD-L1 staining in the tumor had a significantly
higher 5-year survival (Figure 2). However, no
significant relationship existed between the PD-L1 staining
levels in the lymphocytes and the 5-year survival (Figure 3).
Click Here to Zoom
|Figure 2: Survival plot according to PD-L1 staining scores in the
Click Here to Zoom
|Figure 3: Survival plot according to PD-L1 staining scores in
Table I summarizes the relationships between PD-L1
expression levels and the clinical profiles of the patients.
Click Here to Zoom
|Table I: The correlations between PD-L1 expression level and clinical patient profiles.
Expression of CD80
CD80 expression (staining intensity) was detected in 45%
(36/80) of the patients (Table II). CD80 staining scores
(Figure 4A-B) ranged from 0 to 4 in 79% of the patients
(63/80) and from 5 to 6 in 21% of the patients (17/80).
Table III shows the correlations between CD80 expression
levels and the clinical patient profiles.
Click Here to Zoom
|Figure 4: A) Strong membranous immunohistochemical CD80 staining in tumor cells (CD80 x200), B) Weak membranous
immunohistochemical CD80 staining in tumor cells, (CD80 x200), C) Strong membranous immunohistochemical CD86 staining in
tumor cells (CD86 x400), D) Weak membranous immunohistochemical CD86 staining in tumor cells (CD86 x400).
Click Here to Zoom
|Table III: The correlations between CD80 expression level and clinical patient profiles.
When CD80 expression was examined, it was significantly
higher in the superficial spreading melanoma and lentigo
maligna melanoma subtypes than in other subtypes.
CD80 staining scores were higher in superficial spreading
melanoma and lentigo maligna melanoma subtypes when
evaluating CD80 staining scores.
CD80 expression (staining intensity) and staining scores
were higher in patients with Breslow thickness below 2 mm.
The positivity for CD80 expression was higher in patients
who did not have tumor ulceration.
CD80 expression was found to be higher in cases of regression.
CD80 expression was higher in patients who did not
have lymph node metastasis. CD80 expression and staining
scores were higher in clinical stage 1-2 cases. Cases with
positive CD80 expression had a significantly higher 5-year
survival rate (Figures 5 and 6).
CD86 expression was found in 46.25% of the cases (37/80)
(Table II). CD86 staining (Figure 4C-D) scores ranged
from 0 to 4 points (64/80) in 80% of the patients and from
5 to 6 points in 20% (16/80).
Table IV shows the correlations between CD86 expression
levels and the clinical profiles of the patients. When CD86
expression was examined, it was significantly higher in
superficial spreading melanoma and lentigo maligna melanoma
than in other subtypes.
Click Here to Zoom
|Table IV: The correlations between CD86 expression level and clinical patient profiles.
CD86 expression and a higher CD86 staining intensity
score were found in patients with a Breslow thickness of
less than 2mm.
CD86 expression was significantly higher in tumors that
did not have ulceration. The expression of CD86 was higher
in patients who did not have lymph node metastasis.
CD86 expression and CD86 staining scores were significantly
higher in pathological Stages 1-2 cases.
While patients with positive CD86 expression had a significantly
higher 5-year survival rate, there was no correlation
between staining score and survival (Figure 7,8).
The simultaneous presence of CD80 and CD86 positivity
or negativity was found to be significantly higher (there
was concurrent CD86 expression in cases with CD80
expression or absent CD86 expression in cases without
Malignant melanoma is a highly immunogenic tumor
and its progression, treatment, and prognosis are directly
related to this feature1
. Antagonistic monoclonal antibodies
against CTLA-4 and PD-1 have been introduced for
immune checkpoint blockade. These agents’ anti-tumor activities have been demonstrated in Phase I, II, and III
studies, with CTLA-4 and PD-L1 standing out as the primary
molecules targeted by immunotherapy modalities
Although most studies on the inhibitory or stimulatory
effects of signal-2 in the formation of the immune response
focus on the two molecules mentioned above, the results of the CD80/CD86-CD28 interaction on immune modulation
are also known.
Our retrospective clinical study investigated the association
between CD80, CD86, and PD-L1 expression, tumor
characteristics, prognostic factors, and survival in cutaneous
In the patients enrolled in our study, no significant relationship
was found between the tumor size and Clark level,
as well as the CD80, CD86, and PD-L1 expression levels.
However, it has been suggested that the immune response
to the tumor effects the vertical growth phase rather than
the radial growth phase because the mortality rate is high
in patients with a Breslow thickness of 2 mm or more, and
the expression of CD80 and CD86 is significantly lower in
There was no statistically significant relationship between
PD-L1 staining intensity and Breslow thickness. However,
the Breslow thickness was significantly higher in patients
with strong PD-L1 expression compared to those with weak
expression in Hino and colleagues’ study15. In addition,
PD-L1 expression was also associated with vertical growth
pattern, Clark level status, and lymph node metastasis but
not with age, sex, or histologic subtype in the same study15.
Hino and colleagues found no link between ulceration and
PD-L1 expression, and Massi and colleagues found ulceration
to be a poor predictor of survival. Their findings were
consistent with ours15,16.
Our study discovered no link between lymphocytic infiltration
and mortality, nor between CD80, CD86, and PD-L1
expression and lymphocytic infiltration. Consistent with
our findings, Massi and colleagues reported no relationship
between lymphocytic infiltration and PD-L1 expression. In
addition, no significant relationship between lymphocytic
infiltration and survival was found in the reports of Gadiot
PD-L1 expression has been identified in melanoma, ovarian
tumors, lung tumors, renal cell tumors, urothelial
tumors, squamous cell carcinomas of the head and neck,
esophageal tumors, cervical tumors, breast tumors, pancreatic
tumors, stomach tumors, Wilms tumors, and glioblastoma,
as well as infiltrating lymphocytes15,19-30.
The literature has no consensus regarding the relationship
between membranous expression and survival. While several
studies have found PD-L1 expression in tumors to be
statistically significantly associated with poor prognosis
and survival16,19,31-36, some studies show the opposite18,24,29.
Similar to previous research suggesting that PD-L1 in
tumor cells can be used as a poor prognostic marker based
on the presence or absence of staining, we found that strong
staining of PD-L1 in tumor tissue indicated poor prognosis
and survival. However, this was not found with PD-L1
expression in TIL. There is little evidence in the literature
to support the use of CD80 and CD86 immunohistochemistry
in tumor immunity and prognosis. While most rodent
tumors have been reported to lack tumor expression of
CD80 and CD8637,38, molecular, immunohistochemical,
and flow cytometry studies have revealed the presence
of CD80 and CD86 in tumor cells in some human tumor
PD-L1 expression in tumor cells and lymphocytes was
associated with a poor prognosis in a study evaluating the
expression of CD80, CD86, and PD-L1 in both the tumor
and lymphocytes in renal cell tumor cases in the literature,
whereas CD80 and CD86 expressions were not correlated
with the prognosis2. In support of these reports, publications
indicate that CD80 and CD86 expression in melanoma
patients does not effect the prognosis42.
CD80 and CD86 expression on the cell surface was significantly
positive in cases with Breslow thickness less than
2mm, no ulceration on the tumor surface, clinical stage
I-II, and no lymph node metastasis in our study. Furthermore,
CD80 and CD86 positivity was found to indicate a
When analyzed, only CD80 positivity and the presence of
regression had a significant relationship. The failure to see
any significant relationship for CD86 positivity is likely due
to a small sample size.
Histologic subtype analysis revealed that CD80 and CD86
expression was significantly higher in superficial spreading
melanoma and lentigo maligna melanoma.
Based on our findings, we recommend using PD-L1,
expressed in tumor tissue, as a prognostic marker in cases
of malignant melanoma, with a high PD-L1 staining score
in the tumor indicating a poor prognosis and determining
the indications for the patient’s clinical management and
immunotherapy. CD80 and CD86 expressions and high
staining scores were statistically significant predictors of a
good prognosis in our study’s survival analysis. As a result,
CD80 and CD86 immunohistochemical markers predict
the prognosis of malignant melanoma cases.
Conflict of Interest
No conflict of interest.
Akdeniz University Scientific Research Projects Unit (Project
Concept: ECA, ICB, Design: ECA, ICB, Data collection or processing:
ECA, ICB, BU, OO, Analysis or Interpretation: ECA, ICB, Literature
search: ECA, Writing: ECA, Approval: ECA, ICB, BU, OO.
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