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.