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N. Casagrande et al.
used a three-dimensional (3D) multicellular heterospher- oid model33 formed by tumor cells, monocytes and MSCs. By using 3D heterospheroids, in which tumor cells and different types of normal cells interact and organize their positions, we found that interactions between MSCs, monocytes and cHL cells increased the overall secretion of CCL5. Maraviroc decreased heterospheroid self- assembling, cell viability and cHL clonogenic growth abil- ity, suggesting that it may counteract TME formation and, as a consequence, its protective effects. In a mouse xenograft model, maraviroc decreased the in vivo growth of both L-540 and L-428 cells by more than 50% and reduced monocyte infiltration without apparent toxicity to the animals. These findings confirm that CCR5 signal- ing contributes to determining the fate of cHL tumor cells.
Recently, Jiao et al.42 demonstrated that maraviroc dra- matically enhanced cell killing of CCR5+ breast cancer cells by the DNA-damaging chemotherapeutic agent doxoru- bicin. Here, maraviroc synergized not only with doxoru- bicin, but also with brentuximab vedotin. These results suggest that CCR5 inhibitors, by enhancing the activity of other drugs, may allow a dose reduction of the two
chemotherapeutic agents already in use in cHL patients. As shown here, CCL5 expression levels positively corre- lated with CD68 levels in cHL tissues, and patients with high CCL5 levels had lower progression-free survival than patients with low or medium expression of this chemokine; this difference may be due to the higher level of macrophages recruited and then reprogrammed by cHL cells towards immunosuppressive tumor-associated PD- L1-positive macrophages as well as by enhanced tumor
growth by CCL5.
In conclusion, in light of the significant reduction of
tumor mass obtained with maraviroc alone, its low toxic- ity and ability to inhibit monocyte infiltration, our results provide the rationale for its clinical assessment in cHL, as a single agent or in combination therapy.
Funding
This work was supported by grant IG 15844 from the Italian Association for Cancer Research (to D.A.) and by an Intramural Grant (5X1000CRO-2011).
Acknowledgments
Valerie Matarese provided scientific editing.
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