CCR4:CCL17 interaction supports clonal cell survival and complements BCR- and TLR-9- mediated cell proliferation in chronic lymphocytic leukemia (149.14)

Abstract Existence and degree of somatic mutation of expressed Ig V genes stratify CLL cases into unmutated (U-CLL) and mutated (M-CLL), clinically distinct subgroups. CLL cells likely receive survival cues via interactions through their BCR, TLR, and cytokine/chemokine receptors. We reported ex vivo expression of CCR4 and its induction on CLL cells stimulated in vitro. In assays of chemotactic behavior in response to CCL17, migrated cells showed significantly higher percentages and densities of CD38 expression than the non-migrated cells suggesting a role for CD38 (a known marker of CLL prognosis) in the CCR4-mediated downstream pathway. Dendritic cell-derived CCL17 may exert an accessory role in BCR- and TLR-9-mediated immune responses in B cells in peripheral organs. CCL17 augmented BCR-mediated B-cell proliferation in 9/16 (56%) U-CLL cases, and in 3/15 (20%) M-CLL cases, and promoted TLR-9-mediated cell proliferation in 13/15(87%) M-CLL cases and 6/16 U-CLL cases. In addition, CCL17 promoted cell survival and down-regulated pro-apoptotic molecules Bid and PUMA in 6/16 cases studied. These pro-survival effects of CCL17 were partially abrogated by the blocking anti-CCR4 mAb (1G1). Taken together, these findings suggest that CCL17 plays a role in modulating BCR- and TLR-9-mediated signaling and migration in CLL. Inhibition of CCR4:CCL17 interaction in vivo could represent a novel therapy by preventing migration of CLL cells towards an environment that promotes their survival.