4.1 CXCL13-CXCR5 promotes tumorigenesis and progression through dual pathways
Tumor immunity has received considerable attention these years, with different immune cells interacting to affect the tumor microenvironment or to fight against tumor cells. Previously, we emphasized T cells and ignored the potential role of B cells in tumor immunity. There is no doubt that B cells, with their closely related chemokine CXCL13, also contribute to tumor progression and inhibition. Studies in recent decades have found the enhanced expression of chemokine ligands and their receptors in many tumors[125–128]. Based on biochemical and molecular biology studies and extensive experiments, we find that the CXCL13-CXCR5 axis is involved in the pro-growth and invasive behavior of several malignancies in many ways, and the mechanisms can be categorized into two types (Fig. 2).
4.1.1 The CXCL13-CXCR5 axis acts directly on tumor cells
The interaction of CXCL13 and CXCR5 expressed on some tumor cells participates in a range of events in tumor development. CXCR5, the G protein-coupled receptor, binds to guanine nucleotides (GDPs) in the stationary state. Following CXCL13 binding, the receptor undergoes a conformational change, resulting in GDP conversion to guanosine triphosphate (GTP) and dissociation of Gα from the trimer to Gαq and Gαi[27–30]. The Gαi and Gβ-Gγ subunits can activate phosphatidylinositol 3‑kinase (PI3K), inducing the Raf/MEK/ERK pathways, integrinβ3-focal adhesion kinase (FAK)/Src-paxillin, and DOCK2/Rac/JNK pathways to modulate tumor cell invasion, growth and migration [30, 128] (Fig. 2). Furthermore, CXCL13 can increase matrix metalloproteinase-9 (MMP-9), enabling tumor cells to invade through endothelial-mesenchymal transition (EMT) [129] (Fig. 2). cancer stem cells (CSCs) are a group of tumor cells with unique morphology and biological behaviors, which share similar characteristics with stem cells: self-renewal and differentiation abilities and high drug resistance[130]. In some cancer species, the CXCL13-CXCR5 axis promotes CSCs to move to lymph nodes and bone marrow and secrete IL-30. Overexpression of IL-30, fostering tumor onset and progression associated with increased proliferation, vascularization and myeloid recruitment, acts as positive feedback to the CXCL13-CXCR5 axis[131].
4.1.2 CXCL13-CXCR5, immune cells, and the tumor microenvironment (TME)
Tumor cells are commonly recognized and destroyed by natural or adaptive elements of the host immune system, and this process is called immune surveillance. In contrast, tumors can evade the host immune system under the cooperation of a broad range of immunosuppressive mediators, particularly myeloid-derived suppressor cells (MDSCs) and T regulatory (Treg) cells[132]. Due to the presence of growth factors and inflammatory mediators under chronic inflammatory conditions, MDSCs are activated to become suppressor cells and impair functions of CD4+, CD8 + T-cell and NK-cell[133, 134]. An interesting study found that Foxp3+ Treg cells could attenuate CD8 + CTL-mediated antitumor immunity[135]. Chemokines usually perform indispensable roles in initiating and executing tumor immune responses and recruiting immunosuppressive cells to the tumor microenvironment[136]. Focusing on CXCL13-CXCR5: (1) The CXCL13-CXCR5 axis assists malignant tumor cells in escaping T effector cell immunity by inducing IL-10. Specifically, we found that regulatory B cells inhibiting the activation of antitumor immune responses via IL-10 could not move to the metastatic microenvironment from CXCL13 knockout mice (experimental data unpublished) (Fig. 2). (2) CXCL13-CXCR5 is also involved in the recruitment of MDSCs and Treg cells, which can promote tumor cell survival, angiogenesis and invasion [134] (Fig. 2).
4.2 CXC13-CXCR5 axis and antitumor effects
The CXCL13-CXCR5 axis mediates the chemotaxis of immune cells in physiological and pathological situations. In tumors, this axis facilitates the migration of immune cells to the tumor microenvironment, which is essential for antitumorigenesis. CXCL13 recruits CXCR5 + B cells and CXCR5 + Tfh cells to the tumor site, resulting in the formation of a tumor TLO[137]. CXCL13-producing CD4 + Tfh cells are observed at a high frequency in tumor-infiltrating lymphocytes (TIL)[138], which may be good prognostic indicators predicting pathological complete remission (pCR) after neoadjuvant chemotherapy[139]. Tfh cells can help to activate adaptive antitumor humoral responses, catalyzing the recruitment of other immune cells (including CD19 + CXCR5 + B cells and CD4 + CXCR5 + T cells) to the tumor and facilitating the formation of TLSs and GCs[140]. The presence of TLO can promote efficient antigen presentation, cell activation and differentiation, initiating and maintaining antitumor T- and B-cell responses, both local and systemic[137].
Previous reports indicated that the presence or absence of CXCR5 might impact the antitumor activities of CD8 + cytotoxic T-lymphocytes[141, 142]. Compared to CXCR5 − CD8 + T cells, CXCR5 + CD8 + T cells showed enhanced proliferative capacity, granzyme B production, tumor necrosis factor-α and interferon-γ expression in different tumor types, provoking more potent tumoricidal effects[143]. Besides, the CXCL13-CXCR5 axis can also be linked to immunodetection sites to enhance antitumor effects. The details will be described in the following tumor types.
4.3 CXCL13-CXCR5 axis in several solid tumors
4.3.1 Lung cancer
Lung cancer, the leading cause of malignancy-related mortality worldwide, can be divided into small cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC)[144]. NSCLC includes adenocarcinoma and squamous carcinoma. In recent decades, studies have revealed the role of CXCL13 and CXCR5 in the development of NSCLC, and their diagnostic values[4, 145–147].
A causative factor of lung cancer is the air environment, with more than 90% of lung cancer cases resulting from cigarette smoke and air pollution. Both contain chemicals referred to as polycyclic aromatic hydrocarbons (PAHs), leading to chronic inflammation of the lungs. Given the oncogene mutations, genomic instability, and enhanced angiogenesis derived from chronic inflammation, lung cancer may experience formation, progression, and metastasis[147, 148]. Wang, Cheng et al. reported the intermediary position of CXCL13-CXCR5 between PAHs and lung cancer. First, the researchers found that both the mRNA and protein levels of CXCL13 increased in a dose- and time-dependent manner after exposure to the representative PAH compound benzo(a)pyrene (BaP)[147]. Then, they sought the mechanism: CXCL13 produced by Ttf1-positive lung cancer cells and Cd68-positive macrophages could bind to AhR (a ligand-activated transcription factor) in the presence of BaP, and the binding site on CXCL13 was the xenobiotic-responsive element. Furthermore, the binding of CXCL13 and CXCR5 expressed in CD68 + macrophages can facilitate tumor-associated macrophages to produce SPP1, and overexpression of SPP1 can increase nuclear expression of B-catenin and facilitate EMT associated with lung cancer progression and metastasis [147] (Table 2).
Table 2
CXCL13-CXCR5 axis in multiple cancers and its therapeutic potential.
Cancer | Pro-cancer | Anti-cancer | Therapeutic potential | Ref |
Lung | ▲Promotion of cancer | ▲Connect with TLS | ▲Knockout of CXCL13 | [147, |
Cancer | proliferation, invasive | Density | ▲SiRNA-mediated | 149, |
| Growth | ▲Co-expression of | silencing decrease CXCL13- | 152] |
| ▲Cancer progression and | CXCR5 with anti- | CXCR5 expression | |
| metastasis for producing | EGFR-CAR-T | | |
| SPP1 | | | |
| ▲Promotion of VCAM-1 | | | |
| expression and cell | | | |
| Migration | | | |
Breast | ▲Be associated with | ▲The recruitment of | ▲CXCL13/CXCR5 | [155, 162, 231, 246] |
Cancer | lymph node metastasis, | CD19 + CXCR5 + B | inhibitors |
| distant metastasis, disease | cells and CD4+ | ▲Inhibitors of downstream |
| stage and weak five-year | CXCR5 + T cells and the | signaling of CXCL13- |
| survival | information of TLS | CXCR5 axis |
| ▲CXCL13-CXCR5- | ▲Patients with higher | | |
| RANKL-PI3Kp110α-Src | expression of CXCL13 | | |
| axis induces EMT and | have better outcomes | | |
| MMP-9 expression | | | |
Gastric | ▲Intra-tumor CXCL13 | N/A | Not studied | [168, 169, 247] |
Cancer | expression correspond to | | |
| larger tumor diameter | | |
| ▲High level of CXCL13 | | | |
| is associated with | | | |
| metastasis, and tumor | | | |
| Grade | | | |
| ▲Recruitment and | | | |
| accumulation of | | | |
| CD40 + MDSC | | | |
Colorectal | ▲CXCL13-CXCR5- | ▲High expression of | ▲SiRNA-mediated | [180, 248–250] |
Cancer | AKT/GSK-3β/β-catenin | CXCL13 and CXCR5 is | knockdown of CXCR5 |
| pathway promotes | related to prolonged | ▲LY294002(inhibitor of |
| epithelial cell growth and | disease-free survival | downstream of CXCL13- | |
| intestinal tumorigenesis | time | CXCR5 axis) | |
| ▲Be correlated with poor | | | |
| Prognosis | | | |
Pancreatic | ▲CXLC13- ERK1/2- | ▲CXCL13/CXCR5 | N/A | [185, 251] |
Cancer | ETV4-CXCR5 leads to | help CD8 + T recruitment | |
| increased migration and | and kill tumor cells | | |
| Invasion | | | |
Prostate | ▲CXCL13-CXCR5- | N/A | ▲SiRNA-mediated | [186, 187, 194, 196, 252] |
Cancer | ERK1/2, PI3K/Akt, | | knockdown of CXCL13 and |
| SAPK/JNK provoke | | CXCR5 |
| invasive and proliferative | | ▲Anti-CXCL13 antibodies |
| Responses | | and anti-CXCR5 antibodies |
| ▲CXCL13-CXCR5- | | ▲Inhibitors that block the |
| LTα:β- LTβR- IKKα/ | | expression of CXCL13 and | |
| STAT3 promotes cancer | | CXCR5: DNA vaccine | |
| growth and progression ▲Androgen/AR-induced | | causes immune imbalance in tumor-associated | |
| overexpression of | | myofibroblasts | |
| CXCL13 is corrected with | | ▲Inhibitors of downstream | |
| tumor cells growth, | | molecules of CXCL13- | |
| proliferation, EMT, | | CXCR5 axis: U-73122(G- | |
| migration, and invasion | | protein β and γ inhibitor), | |
| ▲CXCL13 expression | | ▲LY294002((PI3Kp110 | |
| driven by autocrine HIF- | | inhibitor), Pertussis toxin | |
| 1/TGF-β/SMAD signaling | | (PKC inhibitor) | |
| under hypoxic conditions | | | |
Oral | ▲CXCL13-CXCR5/c- | N/A | ▲ShRNA-mediated | [198, |
Squamous | MYC/NFATc3-RANKL | | knockdown of CXCL13 | 199] |
Cell | promotes MMP-9 | | ▲SiRNA suppression of c- | |
Carcinoma | expression and induces | | Myc | |
| Metastasis | | | |
Clear Cell | ▲The CXCL13+CD8+T | N/A | ▲SiRNA-mediated | [253] |
Renal Cell | cells are associated with | | knockdown of CXCR5 | |
Carcinoma | immunoevasive situation | | | |
| and poor outcomes | | | |
| ▲PI3K/Akt/mTOR | | | |
| pathway promotes | | | |
| proliferation, migration | | | |
| and malignant stage | | | |
High-grade | N/A | ▲CXCL13-CXCR5 | ▲CXCL13 may strengthen | [203, 204, 254] |
Plasma | | induces TLS formation | the answer to anti-PD-1 |
Ovarian | | in tumors and improves | therapy |
Cancer | | tumor immunity | | |
| | ▲CXCL13 can act on | | |
| | CXCR5 + CD8 + T cells | | |
| | to promote the | | |
| | expression of GzmB | | |
| | and IFN-γ | | |
Chronic | ▲CXCR5/LTβR | N/A | ▲Anti-CXCL13 and anti- | [214, 216–219, 255] |
Lymphocytic | /CXCL13 signaling leads | | CXCR5 antibodies |
Leukemia | to protection of | | ▲Inhibitors of downstream |
| abnormally proliferating | | signaling |
| Cells | | | |
| ▲CXCL13 make CLL | | | |
| cells survival by | | | |
| phosphoinositide- | | | |
| PI3K/Akt/FOXO3a | | | |
| Pathway | | | |
| ▲CXCL13-CXCR5- | | | |
| PEG10- caspase-3 and | | | |
| caspase‑8 prevents | | | |
| Apoptosis | | | |
A previous study reported that CXCR5 was overexpressed in adenocarcinoma and squamous tissues than in noncancerous tissues and was associated with tumor stage and nodule involvement[149]. The critical role played by vascular cell adhesion molecule-1 (VCAM-1) in tumorigenesis and metastasis is well understood[150]. The CXCL13:CXCR5 interaction promotes VCAM-1 expression and cell migration via the PLCβ/PKCα/c-Src signaling cascade and NF-κB transcription factors [145]. Inhibition of NF-κB signaling activation by dominant-negative IKKα and IKKβ mutants reduces CXCL13-promoted cell migration and VCAM-1 expression[145].
In lung squamous carcinoma, CXCL13 expressed by TLS-associated perivascular and stromal cells is associated with intratumoural TLS density, which is the most important and independent prognostic marker in untreated patients with lung squamous carcinoma [151]. Due to the high expression of CXCL13 in NSCLC, co-expression of CXCR5 with anti-EGFR-CAR-T cells promotes the migration of T cells to tumor sites, leading to enhanced cytotoxic effects of CAR-T cells on EGFR-CXCL13-positive tumor cells[152]. These data underscore the antitumor effect of CXCL13-CXCR5 signaling, which requires further studies.
4.3.2 Breast cancer
Breast cancer is the most common cancer in females and the leading cause of cancer-related deaths in women[153, 154]. Recent studies have revealed a strong correlation between the CXCL13-CXCR5 axis and breast cancer. CXCL13 is highly expressed in breast cancer tissues and lymph nodes at most normal metastatic sites of breast cancer, while a similar finding was made for CXCR5[155, 156]. High expression levels of both CXCL13 and CXCR5 are associated with lymph node metastasis, distant metastasis, disease stage and poor five-year survival in breast cancer[156]. The spread of tumor cells from the primary focus leads to metastatic disorders, and drives high mortality in breast cancer, the critical components mediating the spread are CXCL13 and CXCR5[157]. Biswas et al. found that both CXCL13 and CXCR5 promoters had RelA binding sites. Of particular note, RelA-treated BCa cells significantly increased the levels of CXCL13 and CXCR5[158]. Furthermore, CXCL13 and CXCR5 possess different harmful regulatory mechanisms: for CXCL13, Nrf2 acts on the Nrf2 binding sites of the CXCL13 promoter to suppress CXCL13 expression. DNA methylation of the CXCR5 promoter can result in transcriptional silencing of CXCR5, and the other reason is the expression of the p53 oncogene, which can drive the downregulation of RelA[158, 159]. Finally, overexpression of CXCL13 and CXCR5 promotes EMT via RANKL-Src-PI3Kp110α and increases vimentin, Snail, Slug, N-cadherin and MMP9 expression and activation, thereby inducing the migration of breast cancer cells [155] (Table 2).
It has been reported that high CXCL13 levels are strongly related to longer survival in HER2-positive cancer patients who are not treated with trastuzumab[160]. In other cases, patients with CXCL13 detected or with high expression generally have better outcomes within invasive triple-negative breast cancer (TNBC)[161]. Recently, emerging studies indicated that high cancer CXCL13 mRNA levels in neoadjuvant GeparSixto treatment were associated with a high pCR rate[162, 163]. Together, these data provide strong evidence that CXCL13 may be a good indicator in some breast cancers.
4.3.3 Digestive system neoplasms
different from other tumors, the tumorigenesis in gastric cancer is associated with the presence of lymph-rich aggregates in the submucosa of the gastric sinus, typical example is the gp130F/F mouse model of gastric cancer[164]. CXCL13 is significantly increased within gastric cancer tissues, mainly in isolated lymphoid follicles and small lymphoid aggregates[165, 166]. As well, intratumor CXCL13 expression corresponds to larger tumor diameter, and the higher relation of CXCL13 with lymph node metastasis and TNM III‑IV is significantly detected than those without lymph node metastasis and TNM I‑II [167, 168]. It was reported that CXCL13-CXCR5-mediated recruitment and accumulation of CD40 + MDSC allowed immune evasion by suppressing T-cell expansion in the tumor microenvironment [169] (Table 2). Furthermore, Jin, K. et al. found that in gastric cancer, high infiltration of CXCL13 + CD8 + T cells, a dysfunctional CD8 + T-cell subpopulation, might be associated with an immune evasion in tumor microenvironment, leading to the poor prognosis and poor therapeutic responsiveness of fluorouracil-based adjuvant chemotherapy[170].
Colorectal cancer (CRC) is the third most common malignancy and the second leading cause of cancer-related deaths worldwide[171, 172]. Given the high expression of CXCL13 in the colon, inflammation occurs, inflammation is an influential agent in CRC development[173, 174]. CXCL13 is high in tumor tissue and is positively linked to a higher clinical stage. Accordingly, the median survival of patients with high CXCL13 expression is shorter than that of patients with low CXCL13 expression[175]. The underlying mechanism may be that TLR4-NF-κB signaling in DCs promotes CXCL13, invoked by intestinal microbiota translocation. And then the interaction of CXCL13 and CXCR5 regulates the AKT/GSK-3β/β-catenin pathway to upgrade Cyclin D1 and C-myc and support epithelial cell growth and intestinal tumorigenesis [175] (Table 2). In a separate study, Chen et al. found that CXCL13-CXCR5 signaling was involved in tumor immunosuppression by histidine decarboxylase (HDC)-expressing bone marrow cells through regulation of Treg cells directly or indirectly affecting CD8 + T cells[135]. An increasing number of studies have demonstrated that colorectal cancer liver metastasis (CRLM) mediates high colorectal cancer mortality. It is generally accepted that macrophages are the most abundant infiltrating immune-associated stromal cells present in and around tumors[176, 177]. A recent study found that colorectal cancer cell-derived exosomal miR-934 transposed to macrophages and induced M2 macrophage polarization through downregulation of PTEN and activation of the PI3K/AKT signaling pathway. Then, polarized cells can secrete CXCL13, which binds with CXCR5 and positively feeds back into this process. The above processes are favorable for CRLM [178] (Table 2).
It is difficult to detect Pancreatic cancer, a lethal disease with an increasing incidence and poor prognosis, at early stages[179]. Pancreatic cancer cells highly express CXCR5, which can be detected in most of human pancreatic cancers[180]. Structural activation of classical and nonclassical NF-κB is involved in the development of pancreatic cancer, along with an increase in the nonclassical NFκB target genes CCL19, CCL21, CXCL12, CXCL13 and BAFF[181]. ETS variant 4 (ETV4) belongs to the polyoma enhancer activator protein (PEA3) subgroup, which exert a key function in multiple tumorigenesis [182, 183]. Gao et al. discovered that in pancreatic ductal adenocarcinoma, the expression of ETV4, increased by CXCL13 through activation of ERK1/2, could upregulate CXCR5 expression mechanistically by binding directly to the CXCR5 promoter region, and subsequently, the CXCL13:CXCR5 interaction led to fostering migration and invasion [184] (Table 2). Interestingly, a opposite finding is that the CXCL13/CXCR5 axis is beneficial in suppressing immune escape. Tfh cells can reshape the function of the antitumor microenvironment in pancreatic cancer through CXCL13. More than 50% of pancreatic ductal adenocarcinoma-infiltrating CD8 + T cells are CD8 + CXCR5 + T cells, and CXCL13-CXCR5 help these T cells recruit and kill tumor cells, which may be treated in collaboration with PD-L1/PD-1 inhibitors[185]. This evidence suggests that the CXCL13-CXCR5 axis has both tumor-promoting and tumor-suppressing effects on pancreatic ductal carcinoma.
4.3.4 Prostate cancer
Prostate cancer is the most frequently diagnosed solid malignancy in American men. Excessive CXCL13 and CXCR5 are discovered in tumor tissues, and overexpression of CXCL13 in serum can be used as a tumor marker. Furthermore, CXCL13, which is highly detected in human bone marrow endothelial cells and osteoblasts, mediates bone metastasis of prostate cancer in a CXCR5-dependent context[186]. PKCε is an oncogenic member of the PKC family, whose upregulation synergizes with the downregulation of Pten to upregulate CXCL13 expression by the nonclassical NF-κB pathway, although it does not act on CXCR5[187, 188]. Excessive activation of PKCε leads to phosphorylation of ERK, Akt and mTOR, exerting protumor growth via the CXCL13-CXCR5 secretion cycle [187] (Table 2).
It is widely accepted that most prostate cancers are androgen-dependent cancers. Androgens and androgen receptors (ARs) are contributors to prostate cancer and can mediate prostate cancer metastasis[189]. Notably, overexpression of AR can significantly upregulate the level of CXCL13 by acting on the AR binding region of the enhancer of the CXCL13 gene, which shows that CXCL13 exerts its function after the androgen/AR axis[190]. Within LNCaP cells, AR along with CXCL13 can promote ETS-1, Snail and Cyclin B1. ETS-1 and Snail are associated with cell growth, proliferation and EMT. Cyclin B1 contributes to the cell cycle and cellular temporal transition (G2/M) in cell proliferation [190–193] (Table 2). Additionally, CXCL13 serves an essential need in AR-induced migration and invasion of androgen-dependent PCa cells[190, 194]. Interestingly, among androgen-independent prostate cancer cells, CXCL13 promotes tumor migration and invasion, in contrast to AR[190].
In this regard, in parallel with tumor cells, myofibroblasts, which are stromal cells associated with cancer, also produce CXCL13 and are involved in the regulation of prostate cancer. Specifically, for androgen-dependent tissues, androgen depletion causes tissue damage and consequent hypoxia, which activates the secretion of hypoxia-inducible factor-1α (HIF-1α), transforming growth factor-β (TGFβ) family members and connective tissue growth factors, resulting in intense expression of CXCL13 and changes in the tumor environment [195, 196]. The combination of CXCL13 and CXCR5 has been found to contribute to tumor growth and proliferation via a Rac/JNK/c-Jun approach and to tumor invasion according to PI3K/Akt, Src, ERK and FAK approaches [28, 194] (Table 2). In summary, CXCL13, CXCR5 and their upstream and downstream signaling molecules may be potential targets for the treatment of prostate cancer, as well as for other chemotherapies.
4.3.5 Other solid tumors
CXCL13-CXCR5 axis also promotes the development of oral squamous cell carcinoma, clear cell renal cell carcinoma and melanoma. In oral squamous cell carcinoma, concomitant with local bone infiltration/osteolysis, elevated levels of CXCL13 and CXCR5 in the tumor-bone microenvironment further promote RANKL via the c-Myc/NFATc3 pathway [197–199] (Table 2). RANKL, an important osteoclastogenic factor, promotes high MMP-9 expression and induces metastasis of oral squamous cell carcinoma[198]. Besides, Dai et al. detected that CXCL13 was highly expressed in exhausted CD8 + T cells in renal cell cancer. CXCL13 + CD8 + T cells decrease the effective molecules IFN-γ and TNF-α, diminish antitumor function, and increase proliferative capacity, which are associated with immune destruction, implying poor outcomes in patients[200]. Based on previous investigations, CXCL13 was considered a potential marker to predict the prognosis of renal cell carcinoma[201].
High-grade plasma ovarian cancer (HGSC) has a low five-year survival rate, and it is interesting to note that CXCL13 expression is associated with prolonged survival[202, 203]. Specifically, CXCL13 affects the antitumor response by promoting the expression of GzmB and IFN-γ and acting on CXCR5 + CD8 + T cells to enhance cytotoxicity (Table 2). This chemokine also recruits CD20 + B cells and enhances the presence of TLSs[203]. It has been proven more effective for the anti-PD-1 therapy of HGSC because CXCL13 may amplify and invigorate CXCR5 + CD8 + T cells[203, 204].
4.4 CXCL13-CXCR5 axis in lymphoid neoplasms and chronic lymphocytic leukemia
Lymphoid neoplasms and chronic lymphocytic leukemia are hematopoietic system diseases, and the interrelations between lymphoid or leukemic cells and stromal cells in the TME are associated with cell growth, survival and progression. The CXCL13-CXCR5 axis mediates the homing of B cells and Tfh cells, benefiting the construction of lymphatic tissue. It is conceivable that pathological changes in B cells and Tfh cells and proliferative reconfiguration in lymphatic tissue can develop with a functional imbalance of CXCL13-CXCR5 signaling.
4.4.1 Lymphoid neoplasms
The aberrant expression of CXCL13 and/or CXCR5 is intricately linked to B- or T-cell-derived lymphomas. An increasing number of clinical details implicates the association of CXCL13 and/or CXCR5 in the pathogenesis of lymphoid neoplasms. These diseases consist of mucosa-associated lymphoid tissue disease caused by Helicobacter pylori, gastric lymphoma[205], primary intraocular lymphoma[206], cutaneous lymphoma[207], angioimmunoblastic T-cell lymphoma (AITL)[208], primary central nervous system lymphoma (PCNSL)[209], diffuse large B-cell lymphoma (DLBCL)[210, 211] and non-Hodgkin's lymphoma (NHL)[212]. Due to the role of the CXCL13-CXCR5 axis in the formation of the FDC network within AITL, CXCL13 was first proposed as a biomarker for the disorder and included in the diagnostic criteria for AITL in 2016[213]. Similarly, in DLBCL, CXCR5 + CD4 + T cells promote tumor cell survival and proliferation via phosphorylation of STAT3 and STAT1, followed by secretion of IL-10[207, 208, 211].
4.4.2 Chronic lymphocytic leukemia
High expression of CXCL13 was found in chronic lymphocytic leukemia (CLL), characterized by the aggregation of monoclonal CD5 + CD23 + B lymphocytes in the peripheral blood, SLO, and marrow. The current findings on the mechanism of CXCL13-CXCR5 pro-CLL development may be summarized in the following categories:
(1) Protection of abnormally proliferating cells. Enhance studies verify that certain microenvironments in the bone marrow and SLO are protective sites for CLL cells, and CLL cells can aggregate to form pseudofolliculars within SLO [214, 215] (Table 2). Given the significance of CXCL13-CXCR5 in B-cell chemotaxis and SLO architecture, it is not surprising to find that CXCR5 is well expressed on the surface of CLL cells and that CXCL13 allows CLL cells to migrate into SLO, the necessary situation of CLL cell proliferation[214, 216]. CXCR5 + tumor cells can activate stromal cells to secrete CXCL13 by means of LTβR and CXCR5/LTβR/CXCL13 signaling, leading to stromal support of tumor cells and maintenance of the FDC network[217]. The end result is enhanced proliferation of leukemic B cells[217].
(2) Assisting apoptosis-resistance of leukemic cells. This mechanism involves two principal signaling pathways (MAPK-ERK1/2-p90RSK pathway and PI3K-Akt-FOXO3a pathway). CXCL13 and other homeostatic chemokines, including CXCL12, CCL19 and CCL21, promote CLL cell survival mediated through MAPK pathway activation[218]. Equally important, the phosphorylated state of FOXO3a may enhance the resistance of some hematopoietic cells to cell death, with CXCL13 providing strong survival instructions for CLL cells via the phosphoinositide-PI3K/Akt/FOXO3a pathway[219]. CXCL13-CXCR5 together with CCL19-CCR7 increases the expression of paternally expressed gene 10 (PEG10) and stabilizes caspase-3 and caspase‑8 in CLL cells to prevent TNF-α-mediated apoptosis [218] (Table 2).