DISCUSSION
Tumor infiltrating lymphocytes are divided into three major lymphocyte
subsets, namely CD4 + T cells, CD8 + T cells and CD3 lymphocytes
[6]. The CD3 molecule is an important molecular marker on the
surface of mature T cells, and about 95% of mature T cells express CD3
molecules. The CD3 molecule and T cell receptor (TCR) constitute a
TCR/CD3 complex, which plays a key role in T cell stimulation signal
transduction and T cell activation [7]. Therefore, CD3 is considered
to be a specific marker of T cells in immunohistochemical staining. Some
studies have also confirmed that the expression level of CD3 in tumor
tissue may be positively correlated with the immune response level of
patients. A low expression of CD3 in tumor tissue may be associated with
poor T cell function, immune monitoring and immune clearance function
[8]. In other tumors, the local immunohistochemical score of CD3 was
confirmed to be related to the tumor stage and degree of differentiation
[9]. In this study, we did not find a correlation between the
expression of CD3 and the general characteristics of the disease;
however, the small sample size in our study may have affected our
results. Effector CD8 + T cells widely infiltrate many tumor types, such
as colon cancer, ovarian cancer, cervical cancer and malignant melanoma,
and directly kill tumor cells, and have been shown to be effective in
the treatment of malignant melanoma [10]. The corresponding
literature [11] also confirms the significance of CD8 detection in
immunotherapy. However, existing studies have focused on the levels of
CD4 and CD8 lymphocytes in peripheral blood to detect the immune status
of patients during immunotherapy, and this effect has been confirmed
[12]. The increase in CD4 + and CD8 + T cell percentage in melanoma
patients 8–14 weeks after the application of ipilimumab is related to
the improvement in survival rate. The number of infiltrating CD8 + T
cells was positively correlated with the prognosis of tumor patients
[13,14]. In terms of patient survival, some studies have found that
patients with more CD8 + T cell infiltration in malignant melanoma have
longer PFS, which is consistent with the conclusion reported in other
studies that the effective CD8 + T cells are positively correlated with
the prognosis of various tumors [15,16]. This trend was also found
in this study. Although there was no statistically significant
difference between study groups, we could see that the level of
expression of CD8 in tumors affected the PFS of patients.
There are different opinions on the impact of CD4 expression in the
local environment of tumors on the prognosis of patients. Some studies
have shown that patients with high CD4 + T lymphocyte infiltration have
a poor prognosis [17]. Other studies have also shown that the degree
of CD4 + T lymphocyte infiltration is significantly positively
correlated with the prognosis of patients [18]. However, many
studies conclude that the prognosis of cancer patients depends on the
ratio of CD4 + T cells to CD8 + T lymphocytes. Both CD4 + and CD8 + T
lymphocytes maintain a dynamic balance to preserve the stability of the
cellular immune function. They change the local immune microenvironment
of the tissue, aggravate the immunosuppression and weaken the immune
monitoring function, which is conducive to the proliferation of tumor
cells, thus conducive to the progress, invasion or metastasis of the
tumor [19]. It has also been independently confirmed that CD4 + and
CD8 + T lymphocyte infiltration can reflect anti-tumor immune function
to a certain extent, and can be used as a marker for predicting
long-term survival [20]. In this paper, the expression of CD4 and
its correlation with various factors was not statistically significant,
but this may also be related to the sample size in this study.
For the most widely used PD-1/PD-L1 inhibitors at this stage, the
evaluation indexes and predictive markers of these inhibitors have been
the focus of research and exploration for a long time. Some studies have
shown that the expression of PD-L1 in tumors is related to its
immunohistochemical response to PD-1/PD-L1 inhibitors, and this may
become a clinically relevant predictive biomarker [21]. The
correlation between tumor infiltrating lymphocytes and the expression of
PD-1/PD-L1 also reveals the status of local immune activity. In the
microenvironment of melanoma, the upregulation of PD-L1 expression
depends on CD8 + T cells. This is mainly due to the production of CCR4
binding chemokines and the additional contribution of induced
proliferation. The presence of these immunosuppressive factors in
melanoma metastasis is innate and driven by CD8 + T cells [22]. In
the immunohistochemical study of melanoma, the expression of tumor PD-L1
was found in 21% of patients (14/66) [23]. The expression of tumor
PD-L1 was correlated with tumor thickness (P = 0.0041), tumor CD8 (P =
0.0084) and interstitial CD8 (P = 0.0001) T cell counts [23]. The
expression of PD-L1 was correlated with the expression of CD8. Other
studies [24] have also found that the presence of CD8 (+) T cells on
the edge of invasive tumors is associated with the expression of the
PD-1/PD-L1 immunosuppressive axis, and may predict the response to
treatment. Some scholars believe that CD8 + T cell density is the best
predictor of PD-1 inhibition therapy in melanoma. The second best
predictors were PD-1 + density of tumor and infiltration margin, and
PD-L1 + density of tumor and infiltration margin. The CD4 + density of
tumor and infiltration margin were the worst predictors [25].
However, the direct correlation between PD-L1, PD-1, CD3 +, and CD8 +
status and survival rate needs further study.