CXCL13, a kind of homeostasis chemokine, was originally called BCA-1 or BLC. CXCL13 participates in tumor genesis, proliferation, metastasis and survival of cancer cells[4–8]. However, its relations with T cell function, immune infiltration, and prognosis of diverse cancers remain unclear. Therefore, this study examined cancer samples from multiple databases for analysis. As a result, CXCL13 expression was related to the prognosis of different cancers, in particular OV. Moreover, CXCL13 co-expression genes also have significant prognostic significance in ovarian cancer. CXCL13 levels revealed a positive correlation with immune infiltration degree within OV. After examining the associations of gene levels among diverse T cells, CXCL13 was confirmed to significantly relate to many functional T cells within OV, especially exhausted T cells. Therefore, CXCL13 might serve as a candidate prognostic biomarker for OV, which offers a new direction to analyze the associations of CXCL13 expression with T cell function and immune infiltration degree.
The present work analyzed CXCL13 expression with systematic prognosis of diverse cancers based on separate datasets from Oncomine and 33 TCGA-derived cancers from GEPIA2. CXCL13 was differentially expressed between tumor and non-carcinoma samples in diverse cancers. According to Oncomine database-based analysis, CXCL13 expression increased in Bladder cancer, BC, CC, HNC, lymphoma, leukemia, OV, and lung cancer compared to normal tissues, whereas certain datasets indicated that CXCL13 was lowly expressed within CRC, kidney cancer and sarcoma (Figure 1A). However, TCGA-based data analysis revealed that CXCL13 was upregulated in BRCA, CESC, COAD, DLBC, ESCA, HNSC, KIRC, LUAD, LUSC, OV, PAAD, READ, SKCM, STAD, TGCT, THYM, UCEC, and UCS, compared with normal adjacent tissues (Figure 1B). Human Protein Atlas data also verified that CXCL13 expression increased within ovarian cancer, as suggested by Immunohistochemistry (Figure 5D).
The different CXCL13 levels within diverse cancers from diverse databases might reflect different data extraction methods and biological properties. Based on Kaplan-Meier Plotter and GEPIA2 data analysis, CXCL13 downregulation predicted the dismal survival of OV, BRCA, ACC, and HNSC (Figure 2). In addition, based on univariate analysis and multivariate analysis, CXCL13 expression was significantly correlated with TNM, stage of the patient, age, gender, histology, and grade, except for race. CXCL13 level was related to TNM stage, corresponding to LNM degree within OV, and TNM stage exhibited the highest HR (Table 1). Collectively, the above results indicated that CXCL13 might serve as a prognostic marker for OV.
The present work evaluated the association of CXCL13 levels with the immune system based on TISIDB database. According to our findings, CXCL13 was the most significantly related to lymphocytes (including Th1, Act-B, and Act-CD8), immunoinhibitors (such as CTLA4, PDCD1LG2, and TIGIT), MHC molecules (like HLA-B, TAP1, HLA-F), and immunostimulators (such as CD27, CD48, and ICOS). Epigenetic silencing of T1-type chemokines can be a new immune escape mechanism in cancer, while selective epigenetic reprogramming promotes the anti-OV therapeutic effect . Membrane-bound PD-L1 has been the most significant OV biomarker over the last decade, which is induced by TAMs-derived soluble inflammatory factors, resulting in immune invasion . Simultaneous blocking of PD-1-PD-L1and CXCL12- CXCR4 pathways can suppress OV proliferation and avoid immunosuppression . Besides, osteopontin upregulation can increase PD-L1 levels within hepatocellular carcinoma (HCC) cells via the activation of CSF1–CSF1R pathway within macrophages, whereas blocking CSF1/CSF1R avoids TAM tracking. Therefore, CSF1R inhibitors may be used to promote the PD-L1 antibody efficacy together . Consequently, CXCL13, which is related to the above immune molecules, offers a novel target to study immune escape in OV, which can be used to be the immunotherapeutic target for OV.
However, OV is by no means a single disorder, which is further classified as numerous molecular subtypes. According to TISIDB database-based analysis, CXCL13 gene displayed the greatest expression within the immunoreactive subtype, while that within the mesenchymal type ranked the second place, and CXCL13 was lowly expressed within differentiated and proliferative types. Differential CXCL13 expression within OV of diverse immune subtypes was detected. The results suggested that the C2 displayed the greatest expression relative to that in the remaining 3 subtypes. The integrative analysis of CXCL13 gene levels across OV and diverse subtypes from various databases possibly suggests that CXCL13 is closely associated with the immune characteristics in TME.
Given that CXCL13 has an important effect on the immune system and on predicting the prognosis of OV, this study examined the association of CXCL13 with immune infiltration degree within OV (Figure 4A). As a result, CXCL13 upregulation was closely associated with the infiltration degrees of many immune cells, like B cells, CD4+T cells and especially, CD8+ T cells, dendritic cells and neutrophils, which have a stronger correlation levels. Additionally, DC infiltration was significantly correlated with OV prognosis (Figure 4B). The diverse SCNA of CXCL13 did not significantly affect the macrophage immune infiltration degrees within OV (Figure 4C), and we paid attention to the relationship of CXCL13 with immune cells.
As suggested by subsequent analyses on the relationships of CXCL13 with TIIC gene markers, CXCL13 interacted with many immune cells and diverse functional T cells, including central memory T cells, effector T cells, and exhausted T cells (Tables 2 and 3). Since T cell exhaustion accounts for a leading reason for the ineffective anticancer immunity [54–56], the measures for preventing T cell exhaustion represent the keys to anticancer immunotherapy. Based on our results, CXCL13 upregulation showed a positive correlation with several critical genes related to exhausted T cells, such as TIM-3, PD-1, LAG3, TIGIT, and GZMB. These are therapeutic targets for immunotherapy [57, 58].
According to our findings, CXCL13 exerts dual functions, where its upregulation shows a positive correlation with favorable survival of some cancers including OV. In the meantime, it can induce T cell exhaustion that may induce inefficient anticancer immunity. Consequently, CXCL13 has important yet different functions in normal immune development and in the regulation of TME, which deserves further investigation.
This study identified that CXCL13 was related to mast cells within OV, which has not been reported previously. Mast cells exert the effector activity in the case of TH2-skewed autoimmune and allergic inflammation, enhance sufficient inflammatory responses, and activate T cell in cooperation with DCs . Some recent studies suggest that mast cells do significantly affect TME conformation or promote cancer development [60, 61]. In our study, CXCL13 upregulation indicated higher levels of certain critical gene markers (TPSAB1, CPA3, MS4A2) in mast cells, implying that CXCL13 had an important function. Moreover, more studies are needed to examine the related mechanism.