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Advances in Dermatology and Allergology/Postępy Dermatologii i Alergologii
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vol. 39
 
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Original paper

The B7 family molecules in oral squamous cell carcinoma: a systematic review. Part I: B7-H1 (PD-L1) and B7-DC (PD-L2)

Anna Starzyńska
1
,
Aleksandra Sejda
2
,
Łukasz Adamski
1
,
Paulina Adamska
1
,
Rafał Pęksa
3
,
Monika Sakowicz-Burkiewicz
4
,
Piotr Wychowański
5
,
Barbara A. Jereczek-Fossa
6, 7

  1. Department of Oral Surgery, Medical University of Gdansk, Gdansk, Poland
  2. Department of Pathomorphology, University of Warmia and Mazury, Olsztyn, Poland
  3. Department of Pathomorphology, Medical University of Gdansk, Gdansk, Poland
  4. Department of Molecular Medicine, Medical University of Gdansk, Gdansk, Poland
  5. Department of Oral Surgery, Medical University of Warsaw, Warsaw, Poland
  6. Division of Radiotherapy, IEO European Institute of Oncology, IRCCS, Milan, Italy
  7. Department of Oncology and Hemato-oncology, University of Milan, Milan, Italy
Adv Dermatol Allergol 2022; XXXIX (2): 265-274
Online publish date: 2020/10/13
Article file
- The B7 family.pdf  [0.18 MB]
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Introduction

Ninety-five percent of oral neoplasms are diagnosed as squamous cell carcinoma (oral squamous cell carcinoma – OSCC). In 2017, about 390,000 new cases around the world were diagnosed (lip and oral cavity). Men suffer more often than women, especially in the sixth decade of life [14]. This type of cancer mainly affects people living in South-Central Asia, Central and Eastern Europe and in Malaysia [1, 2]. Smoking, betel chewing, alcohol abuse and HPV infection are the main risk factors. There is a systematic increase in the prevalence among women and patients under 50 years of age [3, 4].

In a properly functioning organism, damaged cells undergo apoptosis, a process in which various elements of the immune system participate. The main role is played by T and NK (natural killers) lymphocytes. In tumour pathology, cells gain unlimited ability to divide and survive as a result of changes in their genetic material. Lymphocyte function is the result of a balance between up-regulation (stimulation) and down-regulation (inhibition). Some types of cancers exhibit immunogenicity, i.e. the ability to induce an anti-cancer reaction. There are several molecular mechanisms involved in the regulation of the microenvironment of cancer cells and in the protection against the attack of the immune system [5]. Activation of T cells requires two signals. The first one is T cell receptor (TCR) activation – the major histocompatibility complex (MHC) on antigen-presenting cells (APC). The second signal is based on co-stimulatory molecules such as the B7-CD28 pathway [6].

The B7/CD28 family receptors are found on cells of the immune system. These are tumour infiltrating lymphocytes (TILs). Ligands (B7 proteins) are expressed on APC cells, immune cells, epithelial cells, osteoblasts, fibroblasts and others. In addition, the presence of ligands on tumour cells was detected [7]. The B7 family includes proteins and ligands as shown in Figure 1. The B7/CD28 pathway influences the regulation of the immune response by limiting both time and strength of the inflammatory response. Although the co-stimulation mechanism of the B7/CD28 pathway is not known, monoclonal antibodies are currently used in targeted therapies of malignant tumours, autoimmune and infectious diseases [79].

Figure 1

The B7 family ligands and receptors (? - unknown receptor)

/f/fulltexts/PDIA/41686/PDIA-39-41686-g001_min.jpg

Aim

The aim of this paper was to collect and review the B7 family proteins as prognostic factors in OSCC and to describe their role in aggressive disease progression. This particular study includes B7-H1 (PD-L1) and B7-DC (PD-L2) proteins.

Material and methods

For this review, a systematic search of the literature was conducted in the PubMed, Web of Science, Scopus, Embase, Cochrane Library, and Google Scholar databases to identify papers containing data about the B7 family proteins in OSCC. The PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) were used [10].

PICO for study characteristics was used (P – patient/population/problem; I – intervention/exposure; C – comparison; O – outcome):

P: at least 10 patients with primary oral squamous cell carcinoma;

I: protein expression evaluation;

C: not required;

O: B7 family proteins as prognostic factors in OSCC – only B7-H1 (PD-L1) and B7-DC (PD-L2) proteins.

Inclusion criteria for papers were as follows: at least 10 patients with primary oral squamous cell carcinoma, B7 protein expression evaluation, study conducted only on humans, in the English language, prospective and retrospective studies, clinical studies and immunohistochemical evaluation of B7 protein. Articles were excluded if specimens derived from OSCC recurrences (not primary tumours), was conducted on cell lines, was not conducted on humans, the study group consisted of less than 10 patients, non-B7 family protein expression was evaluated or the study was not in English. Duplicate records as well as letters and papers that did not contain significant information were also excluded.

A retrospective analysis of articles on the B7 family proteins as risk factors in OSCC published from 2011 to 22 May 2020, was performed. Key words: “B7 family and oral cancer/OSCC/oral squamous cell carcinoma”, “PD-1/PD-L1/PD-L2 pathway and oral cancer/OSCC/oral squamous cell carcinoma”, “B7-H1/PD-L1/CD274/PDCD1LG1/B7H1/B7-H/PDCD1L1/PDCD1LG1/PDL1 and oral cancer/OSCC/oral squamous cell carcinoma”, “B7-DC/CD273/PDCD1LG2/B7DC/Btdc/PDCD1L2/PDL2/bA574F11.2 and oral cancer/OSCC/oral squamous cell carcinoma”, “PD1 signal transduction and oral cancer/OSCC/oral squamous cell carcinoma” were used. Articles were screened and sorted based on titles and abstracts. Then articles were evaluated for eligibility. Data extracted from those records were analysed in detail. The following pieces of information were collected: total patient number, occurrence of B7 family alterations in OSCC, correlations with age, gender, grading, primary tumour size (T stage), nodal metastases (N stage), staging, prognostic significance and diagnostic methods (immunohistochemistry and other methods). For randomized studies, the Cochrane Collaboration tool [11] and the methodological index for non-randomized studies (MINORS) were used [12]. The ideal global score for non-comparative studies is 16 and for comparative is 24 [12].

Statistical analysis

Statistical analysis was carried out using the Statistica 13.3 (StatSoft Inc. Tulsa, United States), licensed by the Gdansk Medical University.

Results

In the first step of selection 923 references were identified. 533 records were selected after exclusion of the duplicates. Eventually, 36 articles were included in the systematic review (Figure 2) [1348]. Three studies involved PD-L2 while 35 articles were on PD-L1. The first identified study was published in 2011. Table 1 shows the articles included in the analysis [1348].

Table 1

B7 family genetic alterations in oral squamous cell carcinomas: a review of current studies

No.ReferenceStudy typeTotal patient numberOccurrence of protein expression n patients (%)CorrelationsMethods
AgeGenderGradingPrimary tumour size (T stage)Nodal metastases(N stage)StagingPrognostic significance
B7-H1 (PD-L1):
1Cui et al., 2020 [13]O, R, C34No dataNENENENENENENEIHC
2Meehan et al., 2020 [14]O, R, C67No dataNENENENENENENSIHC
3Quan et al., 2020 [15]O, R, C159No dataNENENENENENEOS – NS
p = 0.742
IHC
4Wilms et al., 2020 [16]O, R-P, C10180 (79.2%)NS
p = 0.494
S
p = 0.019
NENS
p = 0.929
NS
p = 0.286
NS
p = 0.888
OS – S
p = 0.021
DFS – S
p = 0.020
IHC
5Zhao et al., 2020 [17]O, R, C4630 (65.2%)NS
p = 0.829
NS
p = 0.956
NS
p = 0.806
NS
p = 0.052
S
p = 0.009
S
p = 0.011
NEIHC
6Ahmadi et al., 2019 [18]O, R, C25570 (27.5%)NS
p = 0.610
S
p = 0.005
NS
p = 0.760
NS
p = 0.260
NS
p = 0.660
NEOS – NS
p = 0.482
DSS – NS
p = 0.864 DFS – NS
p = 0.731
IHC
7Chen et al., 2019 [19]O, P, C4140 (97.6%)NS
p = 0.088
NS
p = 0.857
S
p = 0.010
NS
p = 0.9414
NS
p = 0.147
NEOS – NS
p = 0.696
DFS – NS
p = 0.210
IHC
8de Vincente et al., 2019 [20]O, R, C1254 (3.2%)NENS
p = 0.530
NS
p = 1.000
NS
p = 0.580
NS
p = 0.570
NS
p = 0.350
DFS – S
p = 0.030
IHC
9Kouketsu et al., 2019 [21]O, R, C10673 (68.9%)NS
p = 0.999
NS
p = 511
NES
p = 0.018
NS
p = 0.472
S
p = 0.010
OS – NSIHC
10Takahashi et al., 2019 [22]O, R, C7746 (60%)NS
p = 0.880
NS
p = 0.360
NS
p = 0.420
NS
p = 0.750
NS
p = 0.790
NS
p = 0.580
PFS – NS
p = 0.540
OS – NS
p = 0.920
IHC
11Tojyo et al., 2019 [23]O, R, C4844 (91.7%)NS
p = 1.000
NS
p = 1.000
NS
p = 0.540
NS
p = 0.520
NS
p = 1.000
NEDFS – NS
p = 0.185
IHC
12Hanna et al., 2018 [24]O, R, C81 (32 females)28 females (87%)NENENENENENEFemale OS – S
p < 0.001
IHC
13Maruse et al., 2018 [25]O, R, C9763 (64.9%)NS
p > 0.050
NS
p > 0.050
NS
p > 0.050
NS
p > 0.050
S
p = 0.050
NS
p > 0.050
NS
p > 0.050
IHC
14Stasikowska-Kanicka et al., 2018 [26]O, R, C7862 (79%)NENENENENENEPP – S
p < 0.011
IHC
15Stasikowska-Kanicka et al., 2018 [27]O, R, C7067 (96%)NENENENENENENEIHC
16Udeabor et al., 2018 [28]O, R, C20No dataNENENENENENENEIHC
17Wirsing et al., 2018 [29]O, R, C7545 (60%)NENENES
p = 0.024
NSNEDSD – NS
p = 0.207
IHC
18Ahn et al., 2017 [30]O, R, C6845 (66%)NS
p > 0.050
NS
p > 0.050
NES
p = 0.002
NS p = 0.648S
p = 0.010
DFS – NS
p = 0.070
OS – S
p = 0.039
IHC
19Feng et al., 2017 [31]O, R, C119No dataNENENENENENEOS – S
p = 0.007
IHC
20Foy et al., 2017 [32]O, R, C44No dataNENENENENENENEIHC
21Groeger et al., 2017 [33]O, P, C1515 (100%)NENENENENENENEIHC
22Hirai et al., 2017 [34]O, P, C24No dataNENENS
0.145
NS
p = 0.873
NS
p = 0.542
NENEIHC
23Kogashiwa et al., 2017 [35]O, R, C8444 (52%)NS
p = 0.492
S
p = 0.010
NENS
p = 0.613
NS
p = 0.734
NS
p = 0.235
OS – S
p = 0.006
PFS – S
p = 0.024
IHC
24Kubota et al., 2017 [36]O, R, C46No dataNENENENENENENEIHC
25Mattox et al., 2017 [37]O, R, C5339 (73%)NENENENENENEOS – NS
p = 0.830
IHC
26Takakura et al., 2017 [38]O, R, C10 (patients without chemothe- rapy)8 (80%)NENENENENENENEIHC
27Troeltzsch et al., 2017 [39]O, R, C8826 (29%)NS
p = 0.349
NS
p = 0.579
NS
p = 0.157
NS
p = 0.831
S
p = 0.039
NEDSS – NS
p = 0.937
IHC
28Weber et al., 2017 [40]O, R, C4535/43 (1.:81.4% increased PD-L1_4);
32/43 (2.:74.4% increased PD-L1_2)
NENE1. G1 vs. G3 – S
p = 0.020
2. G1 vs. G3 – S
p = 0.010
1. NS
p = 0.370
2. NS
p = 0.487
1. S
p < 0.002
2. S
p = 0.003
NS
p > 0.05
NEIHC
29Satgunaseelan et al., 2016 [41]O, R, C21740 (18.4%)NS
p = 0.493
S
p = 0.013
NS
p = 0.060
NS
p = 0.550
NS
p = 0.900
NEDSS – NS
p = 0.960
DFS – NS
p = 0.820
OS – NS
p = 0.930
IHC
30Straub et al., 2016 [42]O, R, C8036 (45%)NS
p > 0.050
NS
p > 0.050
NS
p > 0.050
NS
p > 0.050
NS
p > 0.050
NS
p > 0.050
OS – S
p = 0.010
RFS
p = 0.050
IHC
31Chen et al., 2015 [43]O, R, C218139 (64%)NENENENENENEDFS – NS
p = 0.020
OS – NS
p = 0.110
IHC
32Lin et al., 2015 [44]O, R, C305134 (44%)NS
p = 0.124
S
p = 0.006
NS
p = 0.326
NS
p = 0.316
NS
p = 0.736
NS
p = 0.804
OS – NS
p = 0.083
IHC
33Oliveira-Costa et al., 2015 [45]O, R, C14247/97 (49%)NS
p > 0.050
NS
p > 0.050
NS
p > 0.050
NS
p > 0.050
NS
p > 0.050
NS
p > 0.050
DSS – S
p = 0.044
IHC
34Cho et al., 2011 [46]O, R, C4539 (87%)NS
p = 0.787
NS
p = 0.745
NS
p = 0.158
NS
p = 0.393
NS
p = 0.433
NS
p = 0.736
OS – NS
p = 0.501
IHC
35Malaspina et al., 2011 [47]O, R, C39No dataNENENENENENENEIHC
B7-DC (PD-L2):
1Weber et al., 2019 [48]O, P, C4828/36 (77.8%)NENENS p = 0.130NS p = 0.805NS p = 0.960NENS p = 0.400RT-qPCR
2Groeger et al., 2017 [33]O, P, C1515 (100%)NENENENENENENEIHC
3Kogashiwa et al., 2017 [35]O, R, C8420 (23.8%)NS
p = 0.792
NS p = 1.000NENS
p = 0.373
NS
p = 0.449
S
p = 0.011
PFS – NS
p = 0.350
OS – NS
p = 0.058
IHC

[i] R – retrospective study, P – prospective study, R-P – retro-prospective study, O – observational study, C – cohort study, S – significant, NE – not examined, NS – not significant, OS – overall survival, PP – poor prognosis, DSS – disease-specific survival, DSD – disease-specific death, DFS – disease-free survival, PFS – progression-free survival, RFS – recurrence-free survival, IHC – immunohistochemistry, RT-qPCR – reverse transcription polymerase chain reaction.

Figure 2

PRISMA flow diagram of study selection

/f/fulltexts/PDIA/41686/PDIA-39-41686-g002_min.jpg

All presented papers were observational and cohort-based studies (Tables 2, 3). There were no randomized controlled trials. 86.11% were retrospective (n = 31), 11.11% of the studies were prospective (n = 4) and 2.78% were retro-prospective (n = 1).

Table 2

Results of MINORS for non-comparative studies

No.ReferenceMINORS for non-comparative studies
12345678Score
1Quan et al., 2020 [15]2221012010
2Ahmadi et al., 2019 [18]2221012010
3de Vincente et al., 2019 [20]122000207
4Takahashi et al., 2019 [22]211200208
5Tojyo et al., 2019 [23]2122012010
6Hanna et al., 2018 [24]2122012010
7Maruse et al., 2018 [25]2122012010
8Udeabor et al., 2018 [28]200100205
9Wirsing et al., 2018 [29]2212002110
10Ahn et al., 2017 [30]2122022011
11Feng et al., 2017 [31]0122122010
12Foy et al., 2017 [32]2222012011
13Groeger et al., 2017 [33]212100208
14Hirai et al., 2017 [34]210000205
15Kogashiwa et al., 2017 [35]2221012010
16Kubota et al., 2017 [36]2122012010
17Mattox et al., 2017 [37]112201209
18Takakura et al., 2017 [38]2122012010
19Troeltzsch et al., 2017 [39]222001209
20Satgunaseelan et al., 2016 [41]2222012011
21Straub et al., 2016 [42]2222012011
22Chen et al., 2015 [43]2222012011
23Lin et al., 2015 [44]2122012010
24Oliveira-Costa et al., 2015 [45]2222022012
25Cho et al., 2011 [46]2222012011

[i] 1 – a clearly stated aim, 2 – inclusion of consecutive patients, 3 – prospective data collection, 4 – endpoints appropriate to the aim of the study, 5 – unbiased assessment of the study endpoint, 6 – follow-up period appropriate to the aim of the study, 7 – loss to follow up less than 5%, 8 – prospective calculation of the study size; score: 0 – not reported, 1 – reported but inadequate, 2 – reported and adequate; the ideal global score for comparative studies is 16.

Table 3

Results of MINORS for comparative studies

No.ReferenceMINORS for comparative studies
123456789101112Score
1Cui et al., 2020 [13]2101012000029
2Meehan et al., 2020 [14]20010220011211
3Wilms et al., 2020 [16]20210220012214
4Zhao et al., 2020 [17]12200120112214
5Chen et al., 2019 [19]21220120201215
6Kouketsu et al., 2019 [21]21200020211213
7Weber et al., 2019 [48]21222220201218
8Stasikowska-Kanicka et al., 2018 [26]22200120111214
9Stasikowska-Kanicka et al., 2018 [27]22200120111214
10Weber et al., 2017 [40]21200120111213
11Malaspina et al., 2011 [47]12200120111213

[i] 1 – a clearly stated aim, 2 – inclusion of consecutive patients, 3 – prospective data collection, 4 – endpoints appropriate to the aim of the study, 5 – unbiased assessment of the study endpoint, 6 – follow-up period appropriate to the aim of the study, 7 – loss to follow up less than 5%, 8 – prospective calculation of the study size, 9 – an adequate control group, 10 – contemporary groups, 11 – baseline equivalence of groups, 12 – adequate statistical analyses; score: 0 – not reported, 1 – reported but inadequate, 2 – reported and adequate; the ideal global score for comparative studies is 24.

The biggest study group consisted of 305 patients and the smallest – 10 patients. In total, 3170 patients (excluding duplicates) were analysed in the studies. The occurrence of protein expression was as follows: PD-L1 – 18.4–100% and PD-L2 – 23.8–100%. PD-L1 protein was associated with gender [16, 18, 35, 41, 44], grading [19, 48], primary tumour size (T stage) [21, 29, 30] and metastases in lymph nodes [17, 25, 39, 48]. Staging was correlated with PD-L1 [17, 20, 30] and PD-L2 [33]. Only PD-L1 protein expression proved to be a prognostic factor. Overall survival [16, 24, 31, 35, 42], disease-free survival [16, 20, 45], progression-free survival [35], poor prognosis [26] and recurrence-free survival [42] were correlated with PD-L1 protein expression. Immunohistochemistry was the most commonly used diagnostic method.

Discussion

B7 protein family and the receptors

PD-L1 (B7-H1)/PD-L2 (B7-DC)/PD-1

B7-H1/PD-L1 protein (programmed cell death 1 ligand 1/cluster of differentiation 274/CD274/PDCD1LG1/B7H1/B7-H/PDCD1L1/PDCD1LG1/PDL1) is a type I membrane protein (mass 40 kDa) encoded by the CD274 gene on chromosome 9 (locus 9p24.1). The B7-H1 protein has genes parallel to B7-1 ligand in 21%. PD-L1 has three domains: immunoglobulin constant-like domain (IgC; extracellular), the variable-like domain (IgV; extracellular) and homology domain for PD-1 [8, 49]. Intracellular structures are poorly studied. PD-L1 molecules are more prevalent than PD-L2. The PD-L1 protein suppresses the immune system [5052]. PD-L1 protein is found on activated T lymphocytes, dendritic cells, B lymphocytes, NK cells, monocytes, macrophages, endothelial cells, epithelial cells, fibroblasts, mesenchymal stem cells, syncytiotrophoblasts, islets of Langerhans and neurons. The PD-L1 molecule plays a crucial role in the differentiation of regulatory T lymphocytes. The increase in its status is also associated with chronic inflammation and secretion of interferon γ (IFN-γ) [8, 33, 43, 53, 54]. It can affect the results of treatment of hepatitis B and C [55]. The presence of the PD-L1 protein expression has been demonstrated in glioma, ovarian cancer, renal cancer, head and neck cancer, breast cancer, sigmoid cancer, pancreatic cancer, non-small cell lung cancer and melanoma [53, 56]. Wang et al. demonstrated that PD-L1 positive expression was a prognostic factor for poor disease-specific survival in pancreatic carcinoma [53]. An increase in the response to anti-PD-1/PD-L1 therapies has been demonstrated in the treatment of lung cancer associated with smoking. An increased expression of PD-L1 refers to solid tumours, where it can serve as a defence of the tumour against the immune system [44]. In OSCC, PD-L1 protein expression was correlated with gender [16, 18, 35, 41, 44], grade [19, 48], stage [17, 21, 30], tumour size [21, 29, 30], nodal metastases [25, 26, 3942], distant metastases [25, 26], localisation [41], vascular invasion [28], positive TILs infiltration [39], recurrence [42], disease-specific survival [45], disease-free survival [16, 20, 45], recurrence-free survival [42], overall survival [16, 24, 31, 35, 42], progression-free survival [24] and poor survival [26]. Lin et al. suggested the possibility of using PD-L1 as a prognostic factor especially in smokers and men [44]. No correlation was found between the PD-L1 protein expression and betel chewing, alcohol consumption, perineural invasion, depth of invasion, treatment, or distant metastases [41, 44]. A high expression is associated with better overall survival [30]. In addition, the presence of PD-L1 and TILs expression has been correlated with better outcome in patients with locally advanced OSCC. In those cases, the risk of recurrence was lower and survival was improved [24, 35].

B7-DC/PD-L2 protein (programmed cell death 1 ligand 2/cluster of differentiation 273/CD273/PDCD1LG2/B7DC/Btdc/PDCD1L2/PDL2/bA574F11.2) is encoded by the PDCD1LG2 gene on chromosome 9 (locus 9p24.1). The B7-DC protein has genes parallel to B7-1 ligand in 23%. PD-L2 has three domains: immunoglobulin constant-like domain (IgC; extracellular), the variable-like domain (IgV; extracellular) and homology domain for PD-1 [8, 57]. Intracellular structures are poorly studied [5052]. PD-L2 protein is found on dendritic cells, B lymphocytes, Th2 cells, monocytes, macrophages, mast cells, hepatocytes and endothelial cells. This protein suppresses the immune system by inhibiting the T cell response through PD-1 binding. The presence of this molecule on tumour cells may cause the tumour resistance to the immune system [7, 8, 58]. PD-L2 expression was correlated with stage, but not associated with tumour size, nodal metastases, grade, progression-free survival or overall survival in OSCC [33, 35, 48].

Programmed cell death protein 1 receptor is a transmembrane protein (PD-1/cluster of differentiation 279/CD279; 50-55 kDa) encoded by the PDCD1 gene on chromosome 2 (locus 2q37.3). It consists of five domains including ITIM (immunoreceptor tyrosine-based inhibitory motif) and ITSM (immunoreceptor tyrosine-based switch motif). The IgV domain has genes parallel to CTLA-4 receptor in 21-33% and to CD28 receptor in 15.6% [8, 59]. The PD-1 receptor is found in activated T cells, B lymphocytes, NK cells, mast cells, macrophages and dendritic cells [60]. PD-1 proteins were not detected in immature T lymphocytes. The presence of PD-1 protein on TILs was revealed more frequently in comparison with peripheral blood. This was regardless of the patient’s age or HPV infection [61]. PD-1 generates an inhibitory signal that regulates the functions of T lymphocytes. This receptor has two known ligands: PD-L1 and PD-L2 [58]. Programmed cell death protein 1 receptor does not directly affect apoptosis or cell survival. PD-1 signals regulate the cellular response, but this is not completely clear. The signalling process is different in B and T lymphocytes. After binding by the PD-1 receptor, the ligand is followed by phosphorylation of tyrosine in the ITSM domain and recruitment of the SHP-2 (Src homology region 2 domain-containing phosphatase-1) and SHP-1 signal molecules (Src homology region 2 domain-containing phosphatase-2). This blocks the activation of PI-3K molecules (phosphatidyl-inositol 3-kinase) and ZAP70 (zeta chain-associated protein kinase 70) [58]. Activation of SHP-2 causes dephosphorylation of the molecule involved in TCR receptor activity and as a result reduces signal and cytokine synthesis [58]. Higher prevalence of PD-1 receptors on activated lymphocytes suggests that it is more important than the CTLA-4 receptor pathway [62]. An inflammatory reaction induces an increase in the expression of PD-L1 and PD-L2 proteins. They can serve as a feedback mechanism to reduce T cell responses in tissues and protect them from auto-aggressive damage. The binding of PD-L1 ligand to PD-1 receptor leads to the inhibition of proliferation and the reduction of IFN-γ and IL-10 cytokine secretion (interleukin 10) by about 80%, and IL-2 (interleukin 2) to the threshold below the reference values. This inhibits the proliferation of lymphocytes and promotes the survival of the cancer cell [63]. The level of PD-1 protein is high on activated lymphocytes, but it quickly decreases after removal of the antigen. However, when lymphocytes have to contend with chronic inflammation (infection or cancer), the expression of PD-1 protein is still high, which causes “exhaustion” of lymphocytes. A high oestrogen level can also induce PD-1 receptors on T cells and APC [64]. The inhibitory effect was found on Th (CD4+; helper cells) and Tc (CD8+; cytotoxic cells) lymphocytes [65]. The presence of the PD-1 protein expression has been demonstrated in bladder cancer [65] and pregnancy-associated melanoma [66]. In OSCC, PD-1 protein expression was correlated with age [30], stage [30], nodal metastases [30], perineural invasion [30] and not related to the disease-free survival [30], recurrence-free survival [42] or overall survival [30, 42]. PD-1 signalling was strongly enriched in never-smokers and never-drinkers [30]. The role of the PD-1/PD-L1 pathway is not limited to the pathogenesis of tumours. This pathway is important in various diseases: insulin-dependent diabetes mellitus, lupus erythematosus, myocarditis, inflammation of the brain and spinal cord, rheumatoid arthritis and inflammatory bowel diseases [67].

B7 pathway inhibition in cancers and OSCC

The B7/CD28 pathway influences the regulation of the immune response by limiting the time and strength of the inflammatory response. Although the co-stimulation mechanism of the B7-CD28 pathway is not known, monoclonal antibodies are currently used in targeted therapies of malignant tumours, autoimmune and infectious diseases. In cancer, CTLA-4 and PD-1 receptors are blocked by ligands (B7-1 and B7-2 for CTLA-4, and PD-L1 and PD-L2 for PD-1). As a result of ligand-receptor binding, neoplastic lesions are not recognized by the immune system. The function of monoclonal antibodies is to block CTLA-4 and PD-1 receptors. As a result, T lymphocytes re-recognize tumour antigens. The immunomodulatory drugs that block the CTLA-4 protein are ipilimumab and tremelimumab, while the PD-1 is blocked by nivolumab, pembrolizumab, pidilizumab, BMS-936559, MEDI4736 (durvalumab) and MPDL3280A [49, 56, 6872]. They are mainly used in the treatment of melanoma [66, 70], lung cancer [66, 70], genitourinary cancer [66] and prostate cancer [72]. Targeted immunotherapy in head and neck melanoma improved survival. Ipilimumab and nivolumab had a better effect together than in monotherapy [56]. Nivolumab was used in a clinical trial of 296 melanoma, non-small-cell lung cancer, prostate cancer, renal cancer, and colorectal cancer patients. The positive tumour response (expression of PD-L1 in > 5% of cells) was seen in 18% of patients with non-small cell lung cancer, 28% with melanoma and in 27% with renal-cell carcinoma [56]. In Carbognin et al. study, nivolumab, pembrolizumab and MPDL3280A were studied in patients with melanoma, lung and genitourinary cancers. The overall response rate was significantly higher in patients with positive PD-L1 expression [68].

The role of immunomodulatory drugs in the treatment of oral cancer remains unclear and requires more research. The oral squamous cell carcinoma is highly immunosuppressive. An anti-PD-1 monoclonal antibody therapy may result in better clinical efficacy in OSCC patients [7375]. Foy et al. studied the clinical response to pembrolizumab in HPV-negative oral squamous cell carcinoma. The PD-L1 protein was overexpressed and the score of response to pembrolizumab was higher in never-smokers and never-drinkers than in smokers and drinkers, although the mutational load was lower in never-smokers and drinkers. The main difference between oral squamous cell carcinoma in never-smokers and never-drinkers when compared to smokers and drinkers, lies in the immune microenvironment, suggesting a higher clinical benefit of PD-L1 inhibition in oral cancer in never-smokers and drinkers. The immune checkpoint inhibitors can probably extend the survival of many patients [32].

Conclusions

The biology of squamous cell carcinoma is unknown. The search for new molecular markers is extremely important. Components of the B7 family are potential objects of research. Any mutations in gene encoding PD-L1 and quantitative changes in the status of PD-L1 protein may have an impact on the prognosis of oral squamous cell carcinoma.

Conflict of interest

The authors declare no conflict of interest.

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