Although the immunotherapy for tumors has exhibited good effects on many cancers including melanoma and small cell lung cancer. However, it is not sensitive to most PC patients to date. Therefore, it is necessary to systematically study the tumor-infiltrating immune cells and immune genes in PC, which will reveal their clinical significances and relationships. In fact, the 5-year survival rate of PC is extremely poor, and the study on immune genes reveals their possible relationships with clinical prognosis, which is contributed to evaluate the OS of PC. In this present study, we obtained the DEG between tumor and non-tumor tissues and studied their interactions. And systematical bioinformatics analysis further explored their molecular mechanisms. Most importantly, according to the screened and differentially expressed IRGs, a separate post-processing feature was proposed to determine immune cell infiltrations and evaluate the potential clinical outcomes of PC patients.
Our analysis for the immune cell compositions according to TCGA and GTEx databases showed that resting CD4 + memory T cells, M0 and M2 macrophages, CD8 T cells and B cells were the main immune cells. Previous studies have shown that PC is described as a cold tumor in the past [14], and the TAM are the most important immune cells in PC tissues, accounting for 15–20% of immune cells [15]. Many other evidences indicated that the tumor-related macrophages were mainly M2 macrophages [16], which could induce the epithelial-mesenchymal transition (EMT) of PC [17]. Meanwhile, these M2 macrophages could also secret some factors including CCL22 and IL-10, thereby suppressing the functions of CD4 + and CD8 + T cells [18–19].In addition, the macrophage-derived exosomes were proved to also induce the drug resistance in PC[20].
It is reported that the intra-tumor CD4 + Th2 cell infiltrates and FoxP3 + Tregs were also related to the decreased survival of PC patients [21]. In addition, the activated Tregs could induce M2-like macrophage differentiation[22], and the depletion of macrophages in KPC mouse model was proved to markedly reduce tumor metastasis and be associated with the reductions of CD4 + and CD25 + T cell levels [23].
In summary, PC is a typical cold tumor, and its immune microenvironment is mainly infiltrated by cancer-promoting CD4 T cells and TAM. The immunotherapy for immune checkpoints such as PD-1 and CTLA4 mainly promotes the immunosuppression for CD8 + T cells, and has a good effect on heat tumors including melanoma and small cell lung cancer. Our study showed that CD4 + T cells were the predominant cells in PC. Therefore, the immunotherapy targeted for suppressing T cells and TAM may be more effective for PC.
Our analysis for immune genes revealed that both differentially expressed and OS-related immune genes were mainly concentrated at the PI3K-Akt signaling pathway. Interestingly, the PI3K-AKTmTOR was proved to be a key signaling pathway to induce PC and be frequently activated in PC [24].
To establish simple and convenient methods to monitor the immune status and predict clinical outcomes of PC patients, an immune-based prognostic signature was proposed with 12 hub IRGs related to OS. No studies on the function and mechanism of TNFSF10, CD2AP, PCDH1, MYEOV, NUSAP1 in PC have been reported. Among them, CD2AP was reported to induce CD4 T cell differentiation [25], and PCDH1 can bind to SMAD3 thus suppressing the TGF-β1-induced gene transcription [26].
TOP2A, a co-activator of β-catenin, activates PC EMT process[27]. And high expression of IL20RB, BUB1B and WNT7A have been reported to have correlation with shorter survival of PC patients [28–31].However, our analysis based on TCGA database demonstrated that high BUB1B expression was related to better prognosis. TPX2 mRNA and protein are highly expressed in PC cells or tumors, and previous studies indicated that the TPX2 knockdown with TPX2-specific RNA could effectively reduce the growth but induce apoptosis of PC cells in media, and suppressed the growth of PC in soft agar and nude mice [32–33].
Among the 12 genes, TYK2 was reported to be positively related to CD4 T cells while RAB27B was negatively related to CD4 T cells [34]. TYK2 belonged to JAK family could activate STAT3 and promote the expressions of the critical genes related to the growth, survival and immunosuppression of tumors [35]. In addition, TYK2 signal was also critical for the IL-23-induced IL-17 secretion in γδ T cells, which could promote the release of IL-27 in macrophages [36]. Meanwhile, IL-27 could lead to markedly increased Th1/Tc1, Th2/Tc2, Th17/Tc17, Th9, and Th22 cells [37]. More importantly, RAB27B was proved to be used as a potential biomarker for metastasis and prognosis of breast cancer and lung adenocarcinoma [38–39], and play significant roles in the invasion, proliferation and apoptosis of PC cells, as well as in chemotherapy resistance [40]. Our study demonstrated that RAB27B expression was also negatively related to CD4 T cell infiltration. But, the function of RAB27B in suppressing CD4 T cells needs to be further studied.