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Maraviroc inhibits cHL crosstalk and xenograft growth
CSF.16 Consistent with the finding that cHL cells secrete M-CSF, the education of monocytes by cHL-cell condi- tioned medium, also without a preconditioning with M- CSF or GM-CSF,16,17 was sufficient to shape monocytes to secrete and express immunosuppressive molecules, including IDO and PD-L1, and to inhibit PHA-activated lymphocyte growth.
Recently, it was found that, in cHL tissues, TAMs are not randomly distributed; in fact, PD-L1+ TAMs lie in greater proximity to PD-L1+ tumor cells and PD1+ T cells preferentially localize in proximity to PD-L1+ TAMs, sug- gesting a model in which the inflammatory microenviron-
ment of cHL is highly organized with PD-L1+ TAMs immediately surrounding Hodgkin and Reed-Sternberg cells to engage PD-1+ T cells and augment immune sup- pression.41 Thus, our results suggest that cHL cells, by inducing PD-L1 expression in monocytes, contribute to the building of the immunosuppressive niche.41 Maraviroc, by reducing monocyte recruitment, may coun- teract this phenomenon.
Since current two-dimensional (2D) in vitro methods often fail to adequately replicate tumor cell interactions with the TME and to properly assess drug activity, here, to evaluate the effects of maraviroc, we developed and
Figure 7. Proposed mechanism for the inhibitory effects of the CCR5 antagonist maraviroc on TME formation and cHL tumor growth. (1) Maraviroc, a CCR5 antag- onist, inhibits the recruitment of monocytes and MSCs by cHL cells (Hodgkin and Reed/Sternberg, HRS). (2) The tumor “education” of MSCs cells (E-MSCs) induces the secretion of CCL5. (3) Maraviroc inhibits the recruitment of monocytes by E-MSCs secreting CCL5. (4) Maraviroc decreases the cHL cell growth-promoting effects of CCR5 ligands secreted by tumor educated-monocytes (E-monocytes) and E-MSCs (CCL5+). (5) Maraviroc inhibits the growth of cHL cells (autocrine growth). (6) cHL: classical Hodgkin lymphoma; HRS: Hodgkin and Reed/Sternberg; MVC: Maraviroc; MSC: Mesenchymal stromal cells; (E)-MSCs: tumor Educated; (E)-monocytes: tumor Educated; TME: tumor microenvironment.
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