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Chemokine receptor expression in MCL is
Chemokine receptor expression in MCL is shown in Table 1. CXCR4, CXCR5 and CCR6 protein was detected in the majority of patients [10], [72], [102], [118] and CX3CR1 was found to be present in up to 75% of cases depending on the method used to identify the receptor [103]. CCR7 was more highly expressed in MCL than normal best quality [71] and its protein expression varied based on anatomical site [118]. CCR1, CCR3 and CXCR3 were also detected in a small percentage of patients [4], [14], [68], [72].
Burkitt lymphoma
Germinal center B cells rely on expression of chemokine receptors CXCR4 and CXCR5 to move between the dark and light zone of the germinal center where proliferation and selection occur, respectively. CXCR5 was discovered in BL and was originally named Burkitt Lymphoma Receptor 1 (BLR1) [122]. Flow cytometry on a small number of samples found that CXCR5 was well expressed in BL patient samples while CXCR4 was expressed in some cases [2]. Multiple CXCR4 inhibitors have shown success inducing cell death in BL cell lines including BKT140 [123], plerixafor and GEZ-644494 [124] and palmitoylated peptides called pepducins [125]. Interestingly, treatment with the CD20 antibody rituximab resulted in increased surface expression of CXCR4 whereas treatment with Shiga-like toxin reduced the amount of CXCR4 available [126].
The prostaglandin E receptors PTGER1, PTGER2, PTGER3 and PTGER4 are believed to play a proinflammatory role in BL [127]. In particular, PTGER4 has been identified on a variety of B cell lymphoblast cell lines, including BL, and is thought to inactivate NF-κB to sensitize cells to chemotherapeutics and induce apoptosis [128]. Other GPCRs which have been identified in BL include the cannabinoid receptor CNR1, which demonstrated strong and uniform staining via IHC in a BL patient sample [51], and the trace amine associated receptor TAAR1 protein, which was detected by Western blot in normal B cells along with a variety of B cell lymphoma cell lines including BL. Treatment of the BL cell line L3055 with a TAAR1 agonist was toxic to the cells via an apoptotic mechanism [129].
Follicular lymphoma
Next generation sequencing technologies have revolutionized the identification of genetic aberrations in NHL and have revealed multiple mutations in GPCRs in FL. Whole exome sequencing identified loss of function mutations in CXCR4 and P2RY8 [130] as well as copy number loss of CXCR4, P2RY8 and S1PR2 in FL [131]. Mutation or copy number loss of these receptors has also been noted as significantly more common in transformed FL compared to non-transformed FL [131], [132]. These studies suggest a tumor suppressive role for these receptors. CXCR4 protein is well-expressed in FL [133] but S1PR2 surface expression is not as highly expressed compared to other NHLs [118]. P2RY8 has also been noted for a fusion to the SOX5 transcription factor in primary splenic FL [134].
Gene expression profiling of FL cases revealed an increase in the GPCRs PTGER4, CX3CR1, GPR183 (also known as Epstein-Barr virus-induced GPCR 2; EBI2) and CNR1 compared to normal tonsillar B cells [103]. Further investigation into the role of cannabinoid receptors in FL found that CNR1 and CNR2 mRNA were both upregulated compared to reactive lymph node tissue but that their expression did not correlate to tumor grade [51]. In addition, CNR2 transcript expression was found to be anatomically controlled as it was significantly upregulated in duodenal as compared to nodal FL [135].
The expression of chemokine receptors in FL is summarized in Table 1. IHC and flow cytometry of patient samples found that CXCR5 is well-expressed in FL [3], [10], [71], [72], [118] and SNPs in CXCR5 were associated with increased risk of FL and subsequent survival [136], [137]. FL cells are known to produce the ligand for CXCR5, CXCL13, and it is believed they express CXCR5 to respond to CXCL13 and form the architecture of lymphoid follicles [138]. Monoclonal antibodies targeting CXCR5 were found to be reactive against primary cutaneous FL but not closely related lymphomas [139] and have been shown to inhibit tumor growth in mouse models [140]. A trifunctional bispecific antibody targeting CXCR5::CD3 suppressed tumor growth and increased survival in a xenograft model of B cell lymphoma by recruiting T cells to CXCR5-expressing B cells and co-stimulating the activation of CD4+ and CD8+ T cells to lyse B cells [140].