Abstract
PD1(programmed cell death protein 1), a molecule negatively regulated by
immunity,is highly expressed in a wide variety of human malignancies
making it an attractive immunotherapeutic target. PD-L1 is one of the
ligands for PD-1 and expressed both on T cells and tumor cells. The
purpose of this study was to investigate the expression levels of PD1,
PD-L1, regulatory T cells (Tregs), identified as
CD4+CD25+CD127-/low,
and related cytokines during the development and progression of cervical
cancer(CC). Through different groups to simulate the process of the
occurrence and development of CC, peripheral blood of each group was
collected, and different indicators were detected by ELISA and flow
analysis. It was found that except for INF-γ, PD1, PD-L1, IL-2, IL6,
IL-10, TGF-β expression increased gradually with the development of CC,
and the differences between groups were statistically significant
(P<0.05). This situation also appears on the tracking of
preoperative CC patients and postoperative follow-up on test results.
And Tregs in peripheral blood, compared with normal control(NC) group,
the expression increased CC group, the PD1 expression in the Tregs
membrane also increases at the same time. In CC tissues, we found an
interesting phenomenon through multiplex immunohistochemical staining
that CD8+ T cells mainly infiltrated in the tumor cell
aggregation area, while CD4+ T cells mainly appeared
around. Therefore, we speculated that CD8+ T cells
mainly played an anti-tumor immune role in CC tumor tissues.
INTRODUCTION
Cervical cancer(CC) is the third most common cancer in women worldwide
and the most frequent gynecological cancer in developing countries(1-3).
The prime causal factor for this cancer is persistent infection with
human papillomavirus(HPV). In most cases, the human immune system can be
aware of HPV infection, and only a small number of women with persistent
high-risk HPV, such as type 16 or 18, will lead to cervical precancerous
lesions and develop into cervical cancer(2,4). CC, like all solid
tumors, can be treated surgically in early or isolated recurrence. The
vast majority of CC is squamous cell carcinoma, which is sensitive to
radiation. Through in vitro and intracavitary radiotherapy, local
cervical cancer reaches the maximum radiation dose of tumor death. And
mid- and late-stage CC tumors are treated with chemoradiotherapy.
Immunotargeted therapy is a new method to treat advanced recurrent or
metastatic CC in recent years(5-8). According to the report, the
prognosis of patients with metastatic CC is poor with a median survival
of 8-13 months(9).
PD1/PD-L1, as a key molecule of immune checkpoint, is an important
target of immunotherapy and has changed the pattern of tumor
treatment(10-11). Especially for patients with terminal and critical
cancer, such as melanoma(12), non-small-cell lung cancer(13), ovarian
cancer(14), breast cancer(15), including CC(9,16). PD1, a member of the
CD28 receptor family, is a co-inhibitory receptor expressed on the cell
surface. PD1 and its ligand PD-L1 bind as an immunocheckpoint to play an
immunosuppressive role(17-18). PD1 and PD-L1 signal pathway activation
contributes to tumor immune escape and provides important negative
signals to limit, terminate or impair T cell immune response, and
blocking the pathway can reduce tumor inhibition of the anti-tumor
immunity effect, to better improve the body’s own immune system to
resist the ability of the tumor. Thereby the signal pathway as
anti-tumor immune and autoimmune diseases such as novel targets for
therapeutic intervention, theoretically PD1 and PD-L1 signal pathway
with ability for the treatment of various types of tumors(19-21).
Therefore, the application value of PD1 and PD-L1 in patients with
cervical cancer is also worth expecting.
Regulatory T cells (Tregs) and PD-1/PD-L1 pathways are both key to
terminate the immune response(22). It is report that targeting endoglin
expressing Tregs in the tumor microenvironment enhances the effect of
PD1 checkpoint inhibitor immunotherapy(23). Tregs are mainly divided
into natural regulatory T cells(n-Tregs) and adaptive regulatory T
cells(a-Tregs). N-Tregs are mainly
CD4+CD25+CD127-/lowor Foxp3+ T cells. Foxp3 is not only a marker molecule
for CD4+CD25+ Treg, but also a key
gene that determines the function of
CD4+CD25+ Treg. A-Tregs are
developed from peripheral naive T cells induced by low doses of antigens
or immunosuppressive cytokines, including Tr1(type 1 regulatory T cell)
and Th3(T helper 3) cells, which mainly secrete IL-10 and TGF-β to play
a negative role in immune regulation(24-29). In this paper, the
expression of n-Tregs in cervical cancer and its correlation with the
expression of PD1/PD-L1 were mainly discussed.
In this study, groups were set to simulate the occurrence and
development of cervical cancer caused by long-term infection of
high-risk HPV. In addition, during the development of cervical cancer,
the expression levels of PD1, PD-L1, regulatory T cells and related
cytokines in the peripheral blood of patients were investigated. At the
same time, the changes of PD1, PD-L1 and related cytokines before and
after operation in patients with cervical cancer treated by surgery were
followed up. This study laid the foundation for further research on the
immune regulation mechanism and immunotherapy of the immunoregulatory
molecule PD1 and its ligand PD-L1 in cervical cancer.