SVI is an independent prognostic factor of PCa, and in general, adjuvant radiotherapy is effective in patients with SVI [9]. However, this study revealed that the higher CD8+ cell count and the lower CD204+ cell count in the SVI area are an indication of the favorable prognosis of cancers with SVI.
Several studies have been reported that CD8+ cell infiltration is associated with better prognosis [10][11]. In other reports, CD8+ cell was also associated with recurrence, progression, or lymph node invasion [12][13]. CD8+ cell may be associated with cancer progression by inhibiting the activity of effector T cells [14][15]. Thus, we had hypothesized that higher infiltration of CD8+ cell could be a favorable prognostic factor of BCR, however, no significant difference was observed in BCR between the higher and lower CD8+ cell count in the main tumor area (Fig. 1a). Then, we focused on the distribution of the CD8+ cell in each tumor slide. CD8+ cell secret cytotoxic molecules and cytokines, including perforin, granzyme, interferon-gamma (IFN-γ), tumor necrosis factor-alpha and so on, which elicit anti-tumor effects. They are released only in the direction of the target cell by identifying cancer antigen-derived epitopes presented on MHC molecules on tumor cells by T cell receptors to avoid non-specific bystander damage to normal tissue [16]. The mechanism might suggest our data that CD8+ cell increased in the SVI area rather than the main tumor area in each unfavorable tumors was correct (Fig. 1b).
On the other hand, tumor-associated macrophage (TAM) infiltration in the tumor microenvironment is directly associated with tumor invasion, nodal status, and clinical stage in some cancers, and TAMs also have been reported to regulate the growth of prostate cancer [17][18][19]. A previous study reported that M2 TAMs inhibit cytotoxic CD8+ cell, resulting in weakened anti-tumor immunity and the CD204 silencing-enhanced tumor cell death was associated with elevated IFN-γ levels in tumor tissue and increased tumor-infiltrating CD8+ cells [20]. We also focused on the distribution of CD204+ cell in each tumor slide as well as CD8+ cell. In our present study, a significant difference between the higher and lower CD204+ cell count in the main tumor area and the SVI area was observed in BCR (Fig. 1c and 1d).
Patients with very high risk PCa, including SVI are usually considered to be candidates for adjuvant therapy [21][22][23]. However, it is uncertain whether all patients need adjuvant therapy, as some of them do not appear to benefit. Therefore, the development of an improved prediction model of the very high risk PCa is necessary and unmet needs. In this study, we assessed the relationship of the distribution of the CD8+ and CD204+ cell. The combination of those different immune cells could be more useful for predicting the prognosis of the very high risk PCa than a single immune cell. This study was derived from a retrospective review of patients treated at two institutions and the specimens used in this study could not reflect all status of the tumor immune microenvironment. The small tumor volume in SVI is also difficult to evaluate. However, the findings obtained in this study could be useful for clinical assessment and decision-making for PCa patients with SVI after RP. It is highly worthwhile to verify these results focused on the different type of immune cells and the marker localization in future prospective studies.
In conclusion, in prostate cancer patients with SVI, the combination of the CD8+ and CD204+ cell infiltration in the SVI area is useful to predict the prognosis.