Abstract
The development of cancer is a multistep and complex process involving interactions between tumor cells and the tumor microenvironment (TME). C-X-C chemokine ligand 13 (CXCL13) and its receptor, CXCR5, make crucial contributions to this process by triggering intracellular signaling cascades in malignant cells and modulating the sophisticated TME in an autocrine or paracrine fashion. The CXCL13/CXCR5 axis has a dominant role in B cell recruitment and tertiary lymphoid structure formation, which activate immune responses against some tumors. In most cancer types, the CXCL13/CXCR5 axis mediates pro-neoplastic immune reactions by recruiting suppressive immune cells into tumor tissues. Tobacco smoke and haze (smohaze) and the carcinogen benzo(a)pyrene induce the secretion of CXCL13 by lung epithelial cells, which contributes to environmental lung carcinogenesis. Interestingly, the knockout of CXCL13 inhibits benzo(a)pyrene-induced lung cancer and azoxymethane/dextran sodium sulfate-induced colorectal cancer in mice. Thus, a better understanding of the context-dependent functions of the CXCL13/CXCR5 axis in tumor tissue and the TME is required to design an efficient immune-based therapy. In this review, we summarize the molecular events and TME alterations caused by CXCL13/CXCR5 and briefly discuss the potentials of agents targeting this axis in different malignant tumors.
Highlights
Chemokines are a family of chemotactic cytokines with small molecular weights (8–14 kDa) [1]
A plethora of functional evidence has demonstrated that CXCL13 and/or CXCR5 participate in the pathogenesis of lymphoma, including mantle cell lymphoma (MCL) [155], follicular lymphoma (FL) [156], diffuse large B-cell lymphoma (DLBCL) [156], primary intraocular lymphoma (PIOL) [157], primary central nervous system lymphoma (PCNSL) [158,159,160], extranodal natural killer (NK)/Tcell lymphoma (ENKTL) [161], and angioimmunoblastic T-cell lymphoma (AITL) [162,163]
CXCL13 expressed by myofibroblasts mediates B-cell recruitment into the tumor microenvironment (TME) [115].In JH−/−mice lacking mature B cells, the emergence and expansion of castration resistant prostate cancer (CRPC) after androgen ablation relies on B cells, rather than T cells, and the CRPC microenvironment is subsequently infiltrated by B cells [115]
Summary
Chemokines are a family of chemotactic cytokines with small molecular weights (8–14 kDa) [1]. Blocking the CXCL13/CXCR5 axis inhibits the migration and localization of B cells to lymphoid follicles, which are called B cell zones in SLOs [13,26,27,34]. In response to CXCL13 secreted by Tfh, FDCs, or marginal reticular cells (MRC), and peripheral CXCR5+ B cells are recruited into the lymphoid follicles or germinal center (GC) in the SLOs through high endothelial venules (HEVs) (Figure 2). The CXCL13/CXCR5 axis connects Tfh cells with B cells These CXCR5-expressing Tfh cells migrate to the lymphoid follicles under the chemotaxis of CXCL13, where they subsequently initiate GC formation, BCR affinity maturation, and B cell differentiation into antibody-producing plasma cells and memory cells by providing costimulatory receptors and cytokines (Figure 2) [40,41,42]. CCXXCCLL1133isissseeccrreetteedd bbyy mmuullttiippleleppooppuulaltaitoinosnosfocfeclleslwlsiwthiitnhtihnetThMe TEM, inEc,liundcilnugdsintrgomstarlomcaelllcse, lelns,deonthdeoltihalelciealllsc,ellylsm, plyhmocpyhteosc,yatneds, taunmdotrucmelolsr.cFeDllsC.,FaDcCon, asidcoenrasbidleesrtarbolme astlrcoemll aplocpe-ll pouplautiloanti,oins ,thisetmheajmorapjorrodpurocedruocferCoXfCCLX13CiLn1t3hienGtChes [G8C5,s86[8].5C,8a6n]c. eCra-anscseorc-iaastseodcfiiabtreodblfaibstrsoblcaasntscocannvecrotntovemrtytoofimbryoobflaibsrtsobanladstsseacrnedtesCecXrCetLe1C3 XinCtoL1th3einTtMo EthuepToMn hEyuppooxniahaynpdoTxGiaFa-βnd T(HscdGteBeiFlmplM-sβeu[En8lsd)a8ttce]ii,menoTltnlufsChl[a[8Dt8t7hi81]oa].0tn,3ChT+[XafC8hvC7De]tL.hi81na+C3fitXtlihutsCramaaLvtloes1erod3-inipininfsrfiitoloatldtrltrsauuaotcmteeidpnodrgriobntTdyits-ouschuectuuelelmdsm([Ta8obnI9ryL]bt),hioPssunsuDumeb1epm+asonCa[p8rDbur9oo8l]a,+wntPeTioeDmcnn1eda+l[l9orCs1rt[hDo]9,ew08nl]+ie,aeTotlnhp(cdeHleaoTlBsltGsthMiF[ce9EβlT0i)a-]l, thceelTlsG[F85β]-,daenpdensedveenrtalCtDyp1e0s3+oCfDtu8m+ tourmceolrls-i.nfiltrating T-cell (TIL) subpopulation [91], neoplastic T cells [85], and several types of tumor cells
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