Although PD-L1 was highly expressed in small-cell lung cancer , urinary tract epithelial carcinoma  and head and neck carcinoma , and these tumor types had shown clinical efficacy in anti-PD-L1 antibody treatment. However, PD-L1 was almost unexpressed or low expressed in primary PRAD  and high-risk prostate cancer tissues . In addition, no efficacy was shown in the treatment of castration-resistant PRAD with anti-PD-L1 antibody . Based on the cohort of 52 adjacent normal tissues and 499 PRAD tumor tissues provided by TCGA database, the down-regulation of CD274 mRNA was also observed in PRAD tumor tissues. In addition, we performed IHC detection of CD274 protein in 200 adjacent normal tissues, 67 M-PRAD tumor tissues and 133 non-M-PRAD tumor tissues. CD274 was down-regulated expression in both M-PRAD and non-M-PRAD tumor tissues compared to adjacent normal tissues substantially, and the expression of CD274 in M-PRAD tumor tissues was substantially lower than that in non-M-PRAD tumor tissues. Immune checkpoint inhibitors tend to be more effective against tumors with high tumor mutation load, such as melanoma and non-small cell lung cancer, the two tumors with the highest average number of mutations . However, based on 7161 PRAD samples provided by the Cbiopotal database, the TMB of CD274 was only 1.3%. Therefore, CD274 was under-expressed in patients with PRAD and may be ineffective against PD-L1 inhibition.
The up-regulated expression of TIGIT has been observed in melanoma, breast cancer, gastric cancer and other malignant tumors . However, the expression of TIGIT in prostate cancer has not been characterized. Compared to adjacent normal tissues, TIGIT protein was substantially up-regulated expression in both M-PRAD and non-M-PRAD tumor tissues, while no difference was found between M-PRAD and non-M-PRAD tumor tissues via IHC detection, and consistent with TCGA-PRAD cohort at mRNA level. Currently, six anti-TIGIT mAbs have started clinical trials, including tiragomab (MTIG7192A; RG6058), AB154, MK-7684, BMS-986207, ASP8374, and ASP8374 . Compared with PD-L1 inhibitors, anti-TIGIT mAb may be a better choice for PRAD patients.
In both our in-house cohort of CD274/TIGIT protein and TCGA cohort of CD274/TIGIT mRNA shown that the differentially expressed CD274 or TIGIT was not suitable for predicting OS in PRAD patients. However, the down-regulated expression of CD274 or up-regulated expression of TIGIT predicted poorer OS in M-PRAD patients in our in-house cohort and SU2C-PCF Dream Team cohort. In humans and mice, CD155 is one of the main ligand of TIGIT, which interacted to inhibit the function of effector T cells and NK cells . In addition, CD274 was the main ligand of PD-1, which interacted to inhibit the function of immune effector cells . Based on the mutiCox risk model of CD274/TIGIT, we divided M-PRAD cohort into risk-high group and risk-low group. Through ssGSEA analysis, we found that compared with risk-low group, TILs, B Cells, DCs, MHC_class_I, and T_cell_co-stimulation were substantially increased but neutrophils were substantially decreased in risk-high group.
In tumor microenvironment, DCs was generally regarded as necessary for T cell-mediated cancer immunity . Normally, tumor-associated DCs captured tumor antigens and activated tumor-specific T cells in draining lymph nodes . However, considering the inhibitory mechanism within the tumor, DCs are usually insufficient to induce effective tumor immunity and depend on a specific subset of DCs . The activation of tumor antigen-specific T cells was effectively stimuli via tumor-associated CD103+ DCs and CD11b+ DCs . However, the release of nitric oxide and arginase I in tumor-associated DCs inhibited the function of tumor-specific T cells . As a carcinogenic driver, STAT3 enhances tumor cell proliferation, survival and invasion, and inhibits the differentiation, maturation and function of DCs [24; 25]. The tumor-derived factor Toll-like receptor 2 stimulates the production of autocrine IL-6 and IL-10 in cDC, and promotes DCs dysfunction . Moreover, after TIGIT interacted with CD155, the antigen presentation ability of CD155+ DCs decreases, and the secretion of co-stimulatory molecules and proinflammatory cytokines decrease, which in turn inhibits the activation of T cells . The up-regulation of PD-L1 can inhibit the killing of DCs by cytotoxic T lymphocytes and inhibit the anti-tumor response . However, Blocking PD-L1 on dendritic cells promotes the secretion of IL-10 by T cells , which impaired the function of DCs . We speculate that DCs in the risk-high group may be immunosuppressive subtypes, and the subtypes of DCs need to be further confirmed.
Generally, tumors can evade T cell responses by down-regulating MHC class I molecules . According to reports, in metastatic uveal melanoma, MHC class I negative has a better prognosis than MHC class I positive . In the process of colonization of colorectal tumor cells in liver tissue, NK cells kill MHC class I negative tumor cells, thereby selecting MHC class I positive tumor cells for metastasis . The possible explanation for this phenomenon is that the complete loss of MHC class I antigen expression makes cells susceptible to NK cell-mediated killing . In the high-risk group, the high expression of MHC I may be beneficial to the metastasis of PRAD tumor cells.
It is well known that B cells promote T cell activation and proliferation through antigen presentation . However, studies have shown that suppressor B cells have the ability to maintain immune tolerance and promote the expression of IL-10 [32; 33]. In this study, we did not classify the subtypes of B cells. The proportion of inhibitory B cells in the risk-high group may increase, and further verification is needed.
T cell co-signaling receptors can transduce positive (co-stimulatory receptors) or negative (co-inhibitory receptors) regulated TCR signals into T cells. However, there is a big gap in the characterization of the unique functions of each co-stimulatory and co-inhibitory receptor . In this study, we initially found that in the risk-high group, the proportion of T_cell_co-stimulation increased, but its underlying mechanism deserves further exploration.
Neutrophils are a plastic heterogeneous population with tumor-promoting and anti-tumor effects. Studies have shown that neutrophils can promote tumor proliferation by secreting elastase, drive angiogenesis by providing secretion of MMP-9, and promote tumor cell metastasis by degrading extracellular matrix . However, tumor-associated neutrophils inhibited tumor cell metastasis by releasing hydrogen Peroxide (H2O2) that kills disseminated tumor cells [36; 37]. Neutrophils may inhibit the metastasis of PRAD cells by releasing H2O2 In metastatic PRAD tumor tissues. In this study, the cell proportion of neutrophils was substantially reduced in the high-risk group, prompting the risk of tumor metastasis.
In summary, we further constructed a mutiCox model based on CD274/TIGIT and the above-mentioned immune cells, and the results showed that it has significance clinical value in predicting OS in M-PRAD patients, and has good sensitivity and specificity via ROC analysis.