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  • CXCR is not only critical in the B cell


    CXCR5 is not only critical in the B cell lineage in FL. A high proportion of CXCR5-expressing follicular helper T cells (TFH) were observed in FL but not in closely related DLBCL [141] and further investigation revealed that FL regulatory T cells (Tregs) used a CXCL13-CXCR5 autocrine loop for positioning and upregulation of additional chemokine receptors [142]. There was also an increase in the number of CXCR5-expressing memory T cells along with changes in specific CXCR5+ memory T cell subsets in particular [143]. Finally, gene expression profiling showed that as a cell transitioned from normal lymph node to reactive lymph node to FL, CXCR5 expression increased in regulatory T cells whereas S1PR1 and CCR7 decreased [142]. While CXCR5 promotes migration towards CXCL13, CXCR4 mediates migration towards CXCL12-producing stromal cells [144] and is expressed on the surface of normal, relapse and transformed FL cells [3], [10], [71], [72], [118], [131], [133], [145]. Multiple therapeutic possibilities involving CXCR4 have been attempted including monoclonal TAPI-1 receptor [139], the pan-PI3K inhibitor BKM120 [146] and crosslinking of LLT1 [147]. CCR1 expression is highly enriched in FL compared to other lymphoid malignancies [14]. Although increased CCR1 mRNA expression was found to be associated with worse outcome in a one study [148], CCR1 protein expression was not correlated with overall survival or disease stage in a larger study [14]. Presentation of FL can vary in anatomical location and multiple chemokine receptors have expression patterns specific to anatomic subtype. CCR9 was found to be significantly more immunopositive in gastrointestinal FL compared to nodal FL and its presence in nodal FL was found to be an indicator for future gastrointestinal involvement [149]. Similarly, CCR6 was expressed in 28/32 (88%) duodenal FL patients as compared to only 14/27 (52%) nodal follicular lymphoma patients via immunohistochemistry [135] although a separate study did not observe CCR6 in any of 17 patient samples [102]. CX3CR1 was identified in 25–80% of cases depending on the method used to identify the receptor [103] and both CX3CR1 and CCR3 mRNA expression were significantly decreased in FL compared to reactive follicular hyperplasia [150]. Individual studies have also concluded that CCR2 protein is expressed in FL [151] whereas CCR7 [118] and CXCR3 are not as highly expressed [4].
    Diffuse large B cell lymphoma The S1P receptor family plays a prominent role in DLBCL. S1PR2 acts as a tumor suppressor in DLBCL and high gene expression of S1PR2 has been identified as a prognostic factor indicating increased likelihood of survival [152]. Sequencing of 106 DLBCL patient samples and cell lines found 28/106 (26%) had a mutation in the 5′ region of the S1PR2 gene within the intron between exons 1 and 2 [153]. Mutations have also been identified in the coding region of the gene and are suspected to be a result of aberrant somatic hypermutation [153], [154], [155]. In an effort to confirm the role of S1PR2 as a driver mutation in DLBCL, knockout of S1PR2 in mice were found to develop spontaneous disease resembling DLBCL [153]. In addition to mutations in S1PR2, polymorphisms in CCR8 were found to be associated with DLBCL and SNPs in CXCR5 were associated with increased DLBCL risk in the GCB subgroup in particular [136]. IHC of tumor samples found that S1PR1 was expressed on 54–58% of primary testicular DLBCL and 13–40% DLBCL not otherwise specified (DLBCL-NOS) cases [156], [157]. S1PR1 expression was an independent indicator of poor outcome in patients with stage I and II DLBCL [156] and for rituximab-treated patients [157]. S1PR1 was shown to colocalize with phospho-STAT3 in ABC patient samples and treatment of mice with lymphoma with the S1P antagonist FTY720 inhibited Stat3 activity and reduced tumor growth [158]. Similarly, knockout of S1PR1 in cell lines reduced tumor growth and invasion after transplant into mice [158].