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Another important finding in the present study is that patients with lymph node metastasis and tumor
grade 3/4 have higher PD-1 by TILs than patients with non-lymph node metastasis and 1/2 tumor grade.
It is known that tumor grade and lymph node metastasis are usually major barriers to cancer treatment.
And patients developed lymph node metastasis and tumor grade 3/4 have lower survival rates. To a certain
extent, PD-1 by TILs may be contributed to the immunosuppression to aggravate the tumor growth and
carcinogenesis, and further negatively affecting patients’ survival. One study in clinical trials showed that
[32]
PD-1-positive tumors tend to be more responsive to anti-PD-1 or anti-PD-L1 therapies . It is reasonable to
suggest that patients with lymph node metastasis and tumor grade 3/4 seem to be more sensitive to anti-PD-1
or anti-PD-L1 antibodies-based therapies.

Besides, PD-L1 expression state is another key point of PD-1/PD-L1-mediated tumor immune escape. In
tumor tissues, PD-1 was mainly expressed by TILs, and PD-L1 was detected by both tumor cells and TILs .
[33]
PD-1 by TILs was significantly correlated with PD-L1 expressed by tumor cells [34,35] . Furthermore, the
findings that PD-L1-positive TILs in cancer provides a suitable microenvironment for the development of
tumor growth and treatment resistance, which was known to be mediated by the induction of activated IL-6
signaling [36,37] . Although immunotherapy using recombinant antibodies and vaccines, such as the therapies
targeting PD-L1/PD-1, have been linked with prognosis and treatment response for a few solid tumors
including a number of GI malignancies [38,39] , the expression of PD-L1 by CIK cells, TILs, and tumor cells
within the tumor microenvironment remains to be elucidated.

Although the quality assessment of included studies is higher, there are still some limitations in the study.
First of all, the quality of included studies is with selection bias due to the deletion of some unqualified
literatures. Secondly, the screening of language is only English and Chinese and could not represent the
whole population. Thirdly, the research objects are mainly cancerous tissues and the potential role of PD-1
in blood specimen remains unclear. Finally, the sample size in some of studies is small and further studies
with larger sample size are still needed.

In conclusion, this meta-analysis demonstrates that PD-1 expressed by TILs is associated with lymph node metastasis
and tumor grade in solid tumor. And more importantly, the prognostic role of PD-1 is variant in different solid
tumors, which assumed that PD-1 by TILs seems to be a potential predictive biomarker and the development of
strategies against the PD-L1/PD-1 axis would be a promising therapeutic target for some solid tumors.

DECLARATIONS
Acknowledgments
We thank Prof. Liang Wang at Medical College of Wisconsin (E-mail: liwang@mcw.edu) to help us polishing
the whole manuscript in English.

Authors’ contributions
Conception and design: Zhang DY, Liu RZ, Ku JW, Ma YH, Yi YJ
Manuscript writing: Zhang DY, Liu RZ, Ku JW, Ma YH
Manuscripts review and editing: Zhang DY

Data source and availability
Data are searched in PubMed, Embase, Web of Science, CNKI and Wanfang databases.

Financial support and sponsorship
This work was funded by the High-Tech Key Projects of Science and Technology of Henan Province
Government (152102310230), the High-Tech Key Projects of High School of Henan Province (17B320012) and
the Doctoral Scientific Fund Project of Nanyang Medical College (2015NYYZBSJJ01).