Introduction
Nasopharyngeal carcinoma (NPC) is distinct from
other head and neck cancers (HNC) given a number
of factors, including Ebstein-Barr Virus (EBV) association,
geographical endemic incidence patterns (in
particular East and Southeast Asia), environmental
and genetic factors, pathology and early hematogenous
spread.[-] Despite the paucity of data on incidence
and survival rates of NPC in non-endemic regions
(NERs), it has been established that negative EBV status,
WHO type I, higher stage, and older age at diagnosis
are significantly associated with increased mortality.
[] Given the radiosensitivity of NPCs and the advances
in radiation therapy (RT), local control has significantly
improved over time, resulting in improved survival.
However, distant metastasis continues to occur
even when disease is locally controlled, necessitating
the development of new therapeutic strategies.[]
Immune checkpoint inhibitors (ICIs) are key in
treating many cancers and may offer a promising option
for NPC. Their exclusion from cornerstone HNC studies
may be due to underlying biological and clinical differences
between NPC and the other type of HNC malignancies.[-] However, the potential for NPC and EBV
coincidence to create a beneficial microimmune environment
for ICIs remains a subject of interest.[] Current
research focuses on how EBV contributes to NPC
by driving cellular changes and immune evasion, as well
as investigating EBV-associated molecules as potential
early detection biomarkers. Understanding the interplay
between EBV and PD-L1 (Programmed cell death
ligand 1)/PD-1(Programmed cell death 1) is crucial for
developing effective prevention and treatment strategies
for NPC and other EBV-related conditions.[,]
A retrospective review of anti PD-1 treatment revealed
that all HNC subgroups, including NPC, exhibited comparable
survival outcomes.[] A meta-analysis revealed
significant advantages in overall survival (OS) with ICIs
use in recurrent and metastatic NPC with anti PD-1 treatment.[] In the context of non-metastatic (NM) settings,
the administration of anti-PD-1 ICI has been demonstrated
to yield encouraging results.[,] However less
is known about ICIs use in EBV negativite disease and in
the setting of adjuvant RT.[] These controversies underscore
the existing knowledge gap concerning the utilization
of ICI in NPC, thereby underscoring the necessity
for further research in this domain.[-]
PD-L1 has emerged as a critical biomarker in cancer
prognosis and treatment response, particularly in
malignancies such as melanoma, non-small cell lung
cancer, and prostate cancer. High levels of PD-L1 expression
are linked to a more aggressive disease course
and poorer OS. This over expression enables cancer
cells to evade immune detection, complicating treatment
strategies. Research indicates that patients with
tumors exhibiting elevated PD-L1 levels often respond
better to ICIs targeting the PD-1/PD-L1 pathway.[]
A controversial issue in the field relates to the correlation
between PD-L1 positivity and survival benefits,
raising questions about the efficacy of PD-L1 as a reliable
biomarker for the prognostication of NPC.[,]
There has been a high degree of consensus among
pathologists regarding the use of Tumor Proportion
Score (TPS) and Combined Positive Score (CPS) to
calculate PD-L1 expression.[] Still, the relationship
between TPS and CPS scores and survival outcomes
in patients with NPC remains unclear. Therefore, this
study aims to elucidate the prognostic significance of
PD-L1 expression and its derived scoring systems, including
TPS and CPS, on survival outcomes in patients
with NM NPC treated with definitive RT or chemoradiotherapy.
Unlike ICI trials, this biomarker-focused
study evaluates standardly treated patients, providing
real-world insight into PD-L1 expression within conventional
therapy. These findings may serve as a foundation
for future studies integrating ICI, supporting
PD-L1's evolving role as both a prognostic marker and
a potential guide for personalized treatment strategies.
Methods
Study Population and Data Collection
This retrospective cohort study included patients with
histologically confirmed NPC, treated at a single tertiary
care hospital between January 2010 and March 2022.
This study was approved by the Clinical Research Ethics
Committee of Necmettin Erbakan University Faculty
of Medicine (Decision number: 2022/3684, Date: 4
March 2022). Eligible patients were adults (≥18 years)
who received RT, with or without chemotherapy, in accordance
with clinical staging and treatment guidelines
at the time of diagnosis.
Patients were excluded if they were younger than
18 years, had a second primary malignancy at the time
of diagnosis (excluding non-melanoma skin cancer),
lacked follow-up data, or did not have available formalin-
fixed paraffin-embedded (FFPE) tumor tissue
for immunohistochemical (IHC) staining. A total of 60
patients were included in the final analysis.
Clinical, pathological, and follow-up data were extracted
from physical and electronic medical records. Patients were monitored every 3 months for 2 years,
then biannually for 3 years, and annually thereafter.
Follow-up included nasopharynx, neck, thoracic and
abdominal CT and/or MRI, along with routine blood
tests. Staging was performed according to the AJCC
8th edition.[] EBV status was determined solely from
diagnostic pathology specimens using IHC; routine
plasma EBV DNA testing was not performed in our institution
and therefore was not included in the analysis.
Laboratory parameters were recorded within 1 month
before (pre-RT) and after (post-RT) RT. The specific
hematologic markers evaluated including neutrophilto-
lymphocyte ratio (NLR), platelet-to-lymphocyte
ratio (PLR), and hemoglobin-to-red cell distribution
width (HRR)-are detailed in Table 1.
Table 1 Pre- and post-radiotherapy laboratory values and t-test results
None of the patients had received ICIs either prior to
or following treatment. RT-related parameters, including
irradiation volumes, total dose, and treatment technique,
were extracted from the treatment planning system.
We analyzed PD-L1 expression, PD-1 expression,
and EBV status. All three markers were assessed using
IHC on primary tumor tissue. PD-L1 was additionally
scored using the TPS and CPS, based on established
criteria. TPS and CPS were calculated by trained pathologists.
TPS was further stratified using a cut-off
value of 43, determined through receiver operating
characteristic (ROC) curve analysis.
Immunohistochemical Preparation and Interpretation
Haematoxylin-Eosin stained preparations obtained
from parafin blocks fixed with 10% formaldehyde solution
and prepared with routine tissue follow-up were
evaluated under a light microscope (Olympus BX43)
for histopathological examination. For immunohistochemical
staining, the block containing the optimal size material that best represented the tumor, had high
histological grade, and minimal necrosis was selected.
To apply PD-L1, PD-1 and EBV IHC stains, threemicron-
thick sections were taken from each selected
paraffin block onto positively charged slides. Sections
from two different samples were mounted on a single
slide. The tissue samples were placed onto lysin slides
and then sent to the Dako Omnis automatic immunohistochemistry
device for deparaffinization and IHC
staining. Deparaffinization was achieved by washing
with a cleaning agent at 25°C for one minuteand with
deionized water for five seconds. PD-1 (IHC001 Clone,
Genome) was used at a dilution of 1:150. The PD-L1
(22C3 Clone, Dako, Omnis) and EBV (CS 1-4 Clone,
Dako, Omnis) were used undiluted. The PD-1 sample
was subjected to 30 minutes of EDTA incubation, the
PD-L1 sample underwent 30 minutes of citrate incubation,
and the EBV sample was incubated in EDTA for 30
minutes. The staining process was conducted in accordance
with standard protocol, following 30 minutes of
antibody incubation for PD-1 and PD-L1 and 20 minutes
for EBV. Subsequent to the drying of the slides, they
were subjected to two cycles of xylene. Balsam (Entellan
Mounting Medium) was utilized as a covering material.
The region exhibiting the minimum of 100 tumor
cells was selected for the interpretation. The quantification
of PD-L1 expression was calculated with two additional
factors: The TPS and CPS, both of which are scored
on a scale from 0 to 100. According to prior descriptions,
the task of calculating TPS and CPS based on PD-L1 expressions
was assigned to the same pathologist.[]
Statistical Analyses
The data was analyzed with IBM SPSS Statistics 26, a
program utilized by experienced statistician. The following
descriptive statistics were calculated: Mean, stan- dard deviation, minimum, and maximum for numerical
variables; and numbers, percentages for categorical variables.
The differences between the groups were analyzed
using independent sample t-tests and chi-square tests.
The repeated measurements were analyzed using dependent
sample t-tests and repeated measures variance
analysis. Finally, the cut-off value for the parameters
was determined using receiver operating characteristics
(ROC) analysis. Furthermore, Kaplan-Maier analysis
and Cox regression analysis were employed to assess
OS in addition to examining the factors that affect these
outcomes. The primary outcomes of interest was OS.
Time-to-event outcome was measured from the end of
radiotherapy to death, or last follow-up. Kaplan?Meier methods and log-rank tests were used, with p<0.05 considered
significant. Radiologic treatment response was
assessed using post-treatment imaging according to RECIST
1.1 criteria and categorized as complete response,
partial response, stable disease, or progressive disease.
Potential confounders considered in the survival analysis
included age, sex, tumor stage, and treatment modality
(RT alone vs. chemoradiotherapy). No formal effect
modification analysis was performed due to sample size
limitations. For the purposes of this study, a p-value of
less than 0.05 was accepted as significant. This retrospective
cohort study was conducted and reported in accordance
with the STROBE (Strengthening the Reporting of
Observational Studies in Epidemiology) guidelines.
Results
A total of 60 patients with NPC were included in this
study. For detailed overview of cancer staging, pathology,
and other clinical factors are summarized in Table 2.
As shown in Table 2, IH staining results were stratified
based on PD-1, EBVand PD-L1 expressions, and
TPS and CPS. The expression of PD-1 was negative for
tumor cells among the entire cohort of patients (n=60).
However, the expression was positive for immune cells
when utilized as an internal control provided in supplementary
materials. EBV was negative 74.1% in the
study population. The cut-off value for TPS stratification
was determined using ROC curve analyses. In this
analysis, the optimal cut off value for TPS was identified
as 43 yielding a sensitivity of 0.789 and specificity
of 0.780. The area under the ROC curve was 0.836 (95%
CI: 0.733?0.939, p=0.000) (Fig. 1). The mean TPS was
65.68±45.97, with a range from 0 to 162. We stratified
TPS into two groups as <43 (n=24), and ?43 (n=36). For
PD-L1 and CPS, ROC curve analysis did not yield reliable
cut-off values. Therefore, a threshold value of 1 was
selected for both markers, based on published literature.[,,-] The mean PD-L1 expression was 11.47
(±20.21), with a range from 0 to 80 and when stratified
into two groups as <1 (n=31), and ≥1 (n=29). The mean
CPS was 14.67±24.59, with a range from 0 to 90 and was
stratified into two groups as <1 (n=30), and ≥1 (n=30).
Fig. 1. The Receiver Operating Characteristic (ROC)
curve to evaluate Tumor Proportion Score (TPS)
expression cut-off in nasopharyngeal cancer.
Table 2 Patient characteristics
Statistically significant differences in gross tumor
volume of the primary nasopharyngeal carcinoma
(GTV-NF, cm³), age, and treatment response were
observed across the PD-L1, CPS, and TPS subgroups
(p<0.05), as shown in Table 2. Specifically, GTV-NF
(cm3) was significantly higher in the PD-L1≥1 group
compared to PD-L1<1. Both GTV-NF (cm3) and age
were significantly higher in the CPS≥1 group compared
to CPS<1. Additionally, the rate of complete
response to treatment was significantly higher in the
TPS?43 subgroup compared to the TPS<43.
Patients demonstrated significant changes in several
laboratory parameters prior to radiation(pre-RT) compared
to after radiation (post-RT) (Table 1). Statistically
significant reductions were observed in White Blood
Cell Count (WBC) (from 7.53±2.22 to 4.81±2.66, p=
0.000), Lymphocyte count (Lymp) (from 1.90±0.75 to
0.43±0.29, p= 0.000), Hemoglobin (Hg) (p=0.000), HRR
(p=0.000), Neutrophil count (Neu) (p=0.014) and Platelet
Count (Plt) (p=0.000). Conversely, Red Cell Distribution
Width (RDW) (p=0.001) and PLR (p=0.000) were
significantly increased after radiation. Furthermore, a
subgroup analysis was conducted to compare the change
in laboratory parameters between pre-RT and post-RT
values within the PD-L1 (<1, ?1), CPS (<1, ≥1), and TPS
(<43, ≥43) subgroups. There were no statistically significant
differences in any of laboratory values comparing
pre-RT and post-RT values within any of these subgroups
(all p>0.05). An independent evaluation of pre-
RT and post-RT laboratory values was performed across
the TPS subgroups (<43 and ≥43). Significant differences
were observed in pre-RT WBC, neutrophil (Neu),
and neutrophil-to-lymphocyte ratio (NLR), as well as
in post-RT lymphocyte (Lymp) values. Specifically, pre-
RT WBC (p=0.012), Neu (p=0.003), and NLR (p=0.024)
were higher in the TPS <43 group, whereas post-RT
Lymp (p=0.022) was lower in the same subgroup.
In addition to subgroup analyses, EBV status, classified
as positive or negative, was also evaluated in relation
to changes in laboratory parameters pre-RT and post-RT.
Unlike the other subgroups, EBV groups demonstrated
a statistically significant difference in Lymp values comparing
prre-RT and post-RT (p=0.017). Specifically, the
post-RT Lymp value was higher in the EBV-negative
group compared to the EBV-positive group.
The mean follow-up durations were 114.5 months for
OS (range 97.2-131.7 months). In subgroup analyses,
patients with TPS≥43 (n=36) had significantly longer estimated
survival outcome, including OS (147.9 months;
95% CI: 135.2?160.6) compared to those with TPS <43
(n=24). Mean survival time was OS: 29.4 months (95% CI: 23.5-35.4). A statistically significant discrepancy was
observed among the TPS subgroups with respect to OS
(p=0.000), as illustrated in Figure 2. In contrast, PD-L1
and CPS expression results did not show any statistically
significant association with survival outcomes.
Fig. 2. Kaplan-Meier survival curves illustrate overall
survival (a), progression-free survival (b), and
metastasis-free survival (c) based on Tumor Proportion
Score (TPS) expression levels.
In the Cox proportional hazards regression analysis,
higher TPS expression (≥43) was significantly associated
with improved overall survival (p<0.001). The hazard
ratio for patients with TPS ?43 was 677.657 (95%
CI: 2.444-187,867.110), indicating a strong protective
effect. There is not any significant correlation between
CPS and TPS values (r=-0.061, p=0.645).
Discussion
In this retrospective, single-center, cohort study, we
found that TPS <43 was associated with poorer outcomes
in terms of OS and the complete response to
treatment. These findings suggest that TPS <43 could
serve as a predictive marker of worse survival and may
indicate the potential need for adjuvant therapy in NM
NPC, pending validation in further studies.
Novel treatment approaches should be explore as
early hematogenous dissemination remains a major
cause of treatment failure. Furthermore, as NPC is less
commonly seen in NER, there remains a substantial
gap in our understanding of its biological behavior
and prognostic markers in these populations.[] Unlike
other tumor types, utilizing PD-L1 expression as
a prognostic factor poses a significant challenge in the context of NPC literature.[,] Unlike previous studies
of patients with metastatic NPC, the present study
did not demonstrate a correlation between CPS and
survival outcomes, though a correlation was found
with TPS.[] This could be because TPS is calculated
based solely on tumor cells and is therefore more applicable
to localized disease. In agreement with the other
published date on IHC previously identifing a higher
NLR count prior to treatment as a poor prognostic
factor in NPC, a higher NLR count is present in our
cohort was found in our TPS<43 subgroup which was
found to have worse survival outcomes.[]
There is emerging literature on the correlation between
PD-L1 expression and tumor volume in other
tumor types, which could provide helpful clinical information
for treatment sequencing and decisionmaking
regarding subsequent treatments.[,] In
this study, we present the first NPC data showing a significant
correlation between tumor volume (GTV-NF)
and both CPS and PD-L1 expression in NM NPC.
Notably, EBV-negative NPC is more frequently observed
in NER, where literature remains limited.[,]
In our study, we found a statistically significant difference
in Lymp count changes between EBV-positive
and EBV-negative groups, with post-RT Lymp levels
being higher in EBV-negative group. This may reflect
differences in host immune response or tumor microenvironment
characteristics related to EBV presence.
Given the emerging role of ICIs in NPC, the observed
lymphocyte elevation in the EBV-negative group post-
RT may point toward a potentially more favorable immunologic
landscape for ICI responsiveness.
While this study provides insights into the predictive
significance of PD-L1, TPS, CPS, and EBV expressions
in NPC, several limitations should be acknowledged.
This was a retrospective, single-center study
with a relatively small cohort, which may limit generalizability.
Potential residual confounding remains,
as peripheral blood cell counts can be influenced by
infections or nutritional status, and PD-1 staining
interpretation did not account for tumor-infiltrating
lymphocyte density. EBV status was assessed solely by
IHC on diagnostic specimens, and plasma EBV DNA
levels were unavailable, preventing a reliable evaluation
of EBV?TPS interactions, particularly given the
small number of EBV-negative cases. Subgroup analyses
are limited by multiple comparisons, small sample
size, and potential confounding from factors such as
tumor volume, age, and stage. Cox regression included
only a restricted set of covariates (age, sex, tumor
stage, treatment modality) to avoid overfitting, leaving residual confounding possible. Extremely wide
hazard ratios and confidence intervals reflect statistical
instability due to the limited number of events.
Effect sizes and confidence intervals were reported
where possible, but survival estimates should be interpreted
with caution. Despite these limitations, the
study provides a basis for future prospective studies
with larger cohorts to evaluate whether TPS, together
with clinical parameters such as GTV-NF, can guide
personalized treatment strategies in NM-NPC, especially
in non-endemic regions.
Conclusion
This study investigates the prognostic relevance of
PD-L1 and its derived TPS in patients with NM-NPC,
focusing on its associations with tumor volume, treatment
response, and survival outcomes. Although PDL1
expression was not was not independently prognostic
in our cohort, prior studies in other malignancies
suggest its potential predictive role, particularly for
response to ICIs. Despite limitations due to the retrospective
design and small sample size, our findings provide
a preliminary foundation for integrating TPS with
clinical and biological parameters to support more
personalized management strategies for NM-NPC,
particularly in non-endemic regions. Larger prospective
studies with comprehensive biomarker assessment
are warranted to validate these observations and clarify
their clinical applicability.
Ethics Committee Approval: The study was approved by the
Necmettin Erbakan University Faculty of Medicine Clinical
Research Ethics Committee (no: 2022/3684, date: 04/03/2022).
Informed Consent: The study was approved by the institutional
ethics committee, and informed consent was waived
due to the retrospective design.
Conflict of Interest Statement: The authors have no conflicts
of interest to declare.
Funding: The Scientific Research Projects Unit of the Necmettin
Erbakan University funded this study under the Project
number 221518037.
Use of AI for Writing Assistance: AI-based tools were used
solely for language editing and grammar correction. No AI
tools were used for the generation of scientific content.
Author Contributions: Concept - T.Y., G.K.; Design - T.Y.,
G.K., S.F.; Supervision - G.K. S.F.; Materials - T.Y., S.T.A.;
Data collection and/or processing - T.Y., S.T.C.; Literature
search - T.Y.; Writing - T.Y.; Critical review - G.K., S.F., S.T.A.
Peer-review: Externally peer-reviewed.
References
Nakanishi Y, Wakisaka N, Kondo S, Endo K, Sugimoto
H, Hatano M, et al. Progression of understanding
for the role of Epstein-Barr virus and management of
nasopharyngeal carcinoma. Cancer Metastasis Rev
2017;36(3):435-47.
Su ZY, Siak PY, Leong CO, Cheah SC. The role of Epstein-
Barr virus in nasopharyngeal carcinoma. Front
Microbiol 2023;14:1116143.
Guven DC, Stephen B, Sahin TK, Cakir IY, Aksoy S.
Immunotherapy in the first-line treatment of advanced
nasopharyngeal carcinoma: A systematic review and
meta-analysis. Laryngoscope 2024;134(1):7-17.
Yu MC, Yuan JM. Epidemiology of nasopharyngeal
carcinoma. Semin Cancer Biol 2002;12(6):421-9.
van Velsen JS, van der Vegt B, Plaat BEC, Langendijk JA,
Epskamp-Kuijpers CCHJ, van Dijk BAC, et al. Nasopharyngeal
carcinoma: Nationwide trends in subtype-specific
incidence and survival over 3 decades in a non-endemic
area. J Cancer Res Clin Oncol 2024;150(2):49.
Ferris RL, Blumenschein G, Jr., Fayette J, Guigay J,
Colevas AD, Licitra L, et al. Nivolumab for recurrent
squamous-cell carcinoma of the head and neck. N
Engl J Med 2016;375(19):1856-67.
Burtness B, Harrington KJ, Greil R, Soulieres D, Tahara
M, de Castro G, Jr., et al. Pembrolizumab alone or with
chemotherapy versus cetuximab with chemotherapy for
recurrent or metastatic squamous cell carcinoma of the
head and neck (KEYNOTE-048): A randomised, open-label,
phase 3 study. Lancet 2019;394(10212):1915-28.
Kong X, Zhang J, Chen S, Wang X, Xi Q, Shen H, et
al. Immune checkpoint inhibitors: Breakthroughs in
cancer treatment. Cancer Biol Med 2024;20240055.
Shiravand Y, Khodadadi F, Kashani SMA, Hosseini-
Fard SR, Hosseini S, Sadeghirad H, et al. Immune
checkpoint inhibitors in cancer therapy. Curr Oncol
2022;29(5):3044-60.
Tsao SW, Tsang CM, Lo KW. Epstein-Barr virus infection
and nasopharyngeal carcinoma. Philos Trans R
Soc Lond B Biol Sci 2017;372(1732):20160270.
Sato Y, Fukuda N, Wang X, Urasaki T, Ohmoto A,
Nakano K, et al. Efficacy of nivolumab for head and
neck cancer patients with primary sites and histological
subtypes excluded from the CheckMate-141 trial.
Cancer Manag Res 2020;12:4161-8.
Yu YF, Lu GZ, Wang RJ, Song YK, Wu SG. Additional
PD-1 inhibitor improves complete response to induction
chemotherapy in locally advanced nasopharyngeal
carcinoma. Front Immunol 2024;15:1415246.
Shi S, Li B, Zhou P, Chen L, Li H, Wang Y, et al. Analysis
of the clinical efficacy and safety of anti-PD-1 immune
checkpoint inhibitors in locally advanced nasopharyngeal
cancer. Cancer Med 2024;13(14):e7359.
Mai HQ, Chen QY, Chen D, Hu C, Yang K, Wen J, et al.
Toripalimab plus chemotherapy for recurrent or metastatic
nasopharyngeal carcinoma: The JUPITER-02
randomized clinical trial. JAMA 2023;330(20):1961-
70.
Yang Y, Pan J, Wang H, Zhao Y, Qu S, Chen N, et al.
Tislelizumab plus chemotherapy as first-line treatment
for recurrent or metastatic nasopharyngeal cancer: A
multicenter phase 3 trial (RATIONALE-309). Cancer
Cell 2023;41(6):1061-72.e4.
Yang Y, Qu S, Li J, Hu C, Xu M, Li W, et al. Camrelizumab
versus placebo in combination with gemcitabine
and cisplatin as first-line treatment for recurrent or
metastatic nasopharyngeal carcinoma (CAPTAIN-1st):
A multicentre, randomised, double-blind, phase 3 trial.
Lancet Oncol 2021;22(8):1162-74.
Mino-Kenudson M. Programmed cell death ligand-1
(PD-L1) expression by immunohistochemistry: Could
it be predictive and/or prognostic in non-small cell
lung cancer? Cancer Biol Med 2016;13(2):157-70.
Huang ZL, Liu S, Wang GN, Zheng SH, Ding SR, Tao
YL, et al. The prognostic significance of PD-L1 and
PD-1 expression in patients with nasopharyngeal carcinoma:
A systematic review and meta-analysis. Cancer
Cell Int 2019;19(1):141.
Sahinli H, Akyürek N, Yılmaz M, Kandemir O, Duran
AO, Kulaçoğlu S, et al. Good prognostic factor in patients
with nonmetastatic nasopharyngeal carcinoma:
Programmed death ligand-1 expression in tumor cells.
J Cancer Res Ther 2020;16(Supplement):S43-7.
Mercier A, Conan-Charlet V, Quintin-Roué I, Doucet
L, Marcorelles P, Uguen A. Reproducibility in PD-L1
immunohistochemistry quantification through the
tumor proportion score and the combined positive
score: Could dual immunostaining help pathologists?
Cancers 2023;15(10):2768.
Lydiatt WM, Patel SG, O"Sullivan B, Brandwein MS,
Ridge JA, Migliacci JC, et al. Head and neck cancers?
Major changes in the American Joint Committee on
cancer eighth edition cancer staging manual. CA Cancer
J Clin 2017;67(2):122-37.
de Ruiter E, Mulder F, Koomen B, Speel EJ, van den
Hout M, de Roest R, et al. Comparison of three PDL1
immunohistochemical assays in head and neck
squamous cell carcinoma (HNSCC). Mod Pathol
2020;34:1125-32.
Cogswell J, Goldberg SM, Gupta AK, Jure-Kunkel
M, Wang XT, Wiggington JM. Cancer immunotherapy
by disrupting PD-1/PD-L1 signaling. Nov 21,
2013. Available at: https://patents.google.com/patent/
US10323093B2/en. Accessed Jan 23, 2025.
Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova
T, Nishimura H, et al. Engagement of the PD-1 immunoinhibitory
receptor by a novel B7 family member
leads to negative regulation of lymphocyte activation. J
Exp Med 2000;192(7):1027-34.
Latchman Y, Wood CR, Chernova T, Chaudhary D,
Borde M, Chernova I, et al. PD-L2 is a second ligand
for PD-1 and inhibits T cell activation. Nat Immunol
2001;2(3):261-8.
Hsu CL, Kuo YC. Abstract 6404: Clinical scenario of
immune checkpoint inhibitor treatment in metastatic
nasopharyngeal carcinoma. Cancer Res 2023;83(7_
Supplement):6404.
Song S, Chen H, Dou X, Wang K, Yan J, Yu C. The prognostic
value of before treatment neutrophil-to-lymphocyte
ratio in nasopharyngeal carcinoma. Eur Arch
Otorhinolaryngol 2022;279(5):2485-92.
Zhang M, Dong Y, Liu H, Wang Y, Zhao S, Xuan Q, et
al. The clinicopathological and prognostic significance
of PD-L1 expression in gastric cancer: A meta-analysis
of 10 studies with 1901 patients. Sci Rep 2016;6:37933.
Han Z, Wang N, Qiao Q, He X, Wang N. Association
of PD-L1 expression with clinicopathologic characters
in gastric cancer: A comprehensive meta-analysis.
Curr Med Chem 2024;31(21):3198-216.
