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Keywords: Programmed cell death protein 1, meta-analysis, solid tumors, prognosis

INTRODUCTION
Programmed cell death protein 1 (PD-1), a member of the CD28 receptor family, is expressed by activated
[1]
lymphocytes and inhibits their proliferation functions after binding to PD-1 ligands such as PD-L1 . The
interactions with PD-1/PD-L1 signaling has been shown to improve clinical outcome and restore functional
[2]
T-cell responses in several cancers .
Although PD-1 has generated increasing interest as a target for immune modulation in cancers, the
prognostic values of PD-1 expressed by tumor-infiltrating lymphocytes (TILs) in solid tumors were still
[3]
unclear . Several previous studies have reported the PD-1 by TILs is more than a predictive biomarker but
as a worse prognosis marker in multiple solid tumors such as gastric cancer , non-small cell lung cancer
[4]
[5]
(NSCLC) , renal cell cancer and nasopharyngeal cancer . Another studies showed that PD-1 expression
[6]
[7]
is associated with favorable survival in breast cancer , glioblastoma , metastatic melanoma , ovarian
[9]
[8]
[10]
[11]
[12]
cancer and primary human papillomavirus-positive head and neck cancers . Furthermore, one study
displayed that the positive expression of PD-1 expression is not correlated with overall survival (OS) for
esophageal squamous cell carcinoma (ESCC) . The different of tissue samples, detection methods and
[13]
evaluation criterions might be partly responsible for the inconsistent results.
And with the development of PD-L1/PD-1 targeted therapy, some predictive and prognostic biomarkers
are crucial to be identified for the option of individualized anti-PD-1 targeted treatment . Therefore, we
[14]
conducted this meta-analysis to comprehensively evaluate the prognostic value of PD-1 by TILs in solid
tumors, which will further facilitate the development of PD-L1/PD-1 immune check-point targeted therapy
and identify novel strategies targeting PD-1.

METHODS
Publication searching
The eligible studies published in PubMed, Embase, Web of Science, CNKI and Wanfang databases were
searched using the following keywords: “programmed cell death 1 receptor” or “PD-1” or “programmed
death 1” or “CD279 antigen” and “cancer” or “tumor” or “neoplasm” or “carcinoma” and “prognosis” or
“outcome” or “survival”. In addition, we also manually screened the reference lists derived from randomized
controlled trials and systematic review to avoid omitting related publications. The search language was
limited to English and Chinese.

Inclusion and exclusion criteria
Inclusion criteria for this meta-analysis are: (1) full text available; (2) study focus on the association of PD-1
with clinicopathological parameters and OS; (3) cohort study, cross-sectional study or case-control study;
(4) sufficient data or higher dots per inch of K-M survival curves. In addition, the exclusion criteria are
as follows: (1) cell or animal studies; (2) case reports or review; (3) conference abstracts or comments;
(4) repeated articles.

Data extraction and quality assessment
Two investigators (Liu RZ and Ku JW) independently extracted the data from the relevant studies. The
disagreements were resolved by consensus. The extracted data are as follows: first author name, publication
year, patient source, cancer type, number of patients, detection method, clinicopathological parameters,
effect size, hazard ratio (HR) and 95% confidence intervals (CI). The quality of eligible studies were assessed
through the Newcastle-Ottawa scale (NOS) method . Study with NOS scores above to 6 point were usually
[15]
considered to be higher quality.