To select individualized therapy, optimize patients’ benefit and develop appropriate follow-up surveillance, it is necessary to characterize the prognostic value immune cells in ccRCC TME thoroughly. Our study showed that CD8 + T cells and PD-L1 high expression levels were associated with poor OS and DFS. In multiple analysis, increased CD8 + T cell was an independent prognostic factor for DFS and increased PD-L1 positive cells was independent prognostic factor for OS.
Prognostic factors in RCC are divided into anatomical, histological, clinical and molecular factors. In clinicopathological characteristics, bigger tumor size and older age were associated with poor DFS and OS. Furhman nuclear grade was considered as an independent factor for shorter survival, which is also confirmed by previous study[15].
PD-L1 is a transmembrane cell surface protein of tumor cells and binds with PD-1 on T cell surface[16].PD-1 and PD-L1 axis can break physiological immune homoeostasis, inhibit immune response and help immune escape[17, 18], PD-L1 is a critical ICIs target to prolong survival of ccRCC patients. In our study, we found that high filtration of PD-L1 positive cells was associated with poor DFS and OS in ccRCC. The result was consistent with previous studies which showed that PD-L1 can be considered as a powerful negative prognostic factor for ccRCC [19, 20]. However, in multivariable analysis, high filtration of PD-L1 positive cells was considered statistically significant for OS exclusively. One possible reason was our results were restricted by limited sample capacity. Another reasonable explanation is that the expression of PD-L1 were associated with different amount and composition of T cells in TILs [21, 22].
T cells are main immune cells in TME and accounts for about 51% including CD4 + and CD8 + T cells [23]. CD8 + T cells are effector T cells in antitumor immune responses. High density of CD8 + T cells infiltration is considered as a positive variable for prognosis in solid tumor. However, CD8 + T cells showed strong negative survival prognostic value in RCC in previous study, consistently with our study founding[12, 24]. There are similar results in other tumors such as salivary gland cancer[25]. One reasonable explanation is that CD8 + T cells can produce factors such as IFN γ to promote expression of PD-L1[26]. PD-L1 with its receptor suppress and exhaust T cells, which destroy tumor immune and help tumor growth and development. The main function of CD4 + T cells is to promote specific CD8 + T cells transforming into functional effector cells [27].Therefore ,it is called helper T cell and play an important role in regulate cell-mediated immunity against tumor. In our study, the prognostic ability of CD 4 + T cells for ccRCC was undefined. Previous studies also showed controversial result for its prognostic prediction ability in solid tumor. Some study found that higher CD4 + T cell density was associated with a positive outcome in colorectal cancer and laryngeal squamous cell carcinoma[28, 29]. On the contrary, Lee, et al. found that CD4 + T cells were associated with significate poor prognosis in RCC [11]. We assumed that the function of CD4 + T cell is unclear based on different tumor microenvironment. Naive CD4 + T cells differentiate into 4 main subtypes caused by different cytokines and transcription factors-Th1, Th2, Th17 and T regulatory (Treg) cells. Th1 induce cellular immunity responses to against tumor by releasing cytokines [30].However, RCC patients with high Th17 have a higher tumor stage and worse prognosis[31]. Tumor heterogeneity with different cytokine may induce different CD4 + T cells subtype transition. Different subtype influence prognosis in many ways. The complicated mechanism is still unclear and more investigations are needed.
This study has several limitations. First, this was a single-center study. The results may have been affected by selection bias. Second, our study had a small sample size and only included patients who underwent tumor resection and were pathologically diagnosed with ccRCC. Third, ccRCC is a mildly indolent tumor, its prognosis is relatively better than that of other malignant tumors. Simultaneously, patients with RN or PN had limited or no metastasis generally, the OS and DFS were relatively long. Therefore, the discrimination of 3-year surveillance may be relatively insufficient. In later study, we will continue to record the survival data of these samples and make investigations.
In conclusion, our investigation found that high filtration of CD 8 + T cell of ccRCC was significantly associated with poor DFS. Increased PD-L1 positive cells were associated with poor OS. They can provide some prognostic data for clinical subsequent therapy for patients with ccRCC.