Docetaxel promotes the generation of anti-tumorigenic human macrophages

Abstract

The taxanes Docetaxel and Paclitaxel are two of the standard chemotherapies for patients with metastatic breast cancer. The functional effect of Docetaxel and Paclitaxel on human innate immune cells of the myeloid lineage is not well established, nor is the effects these agents have on differentiation of monocytes into macrophages and dendritic cells. Therefore, the aim with this project was to determine the effects of Docetaxel and Paclitaxel on primary human monocyte differentiation, activation and function. For this purpose, primary human monocytes were isolated from healthy donors and cultured with or without Docetaxel and Paclitaxel. We found that Docetaxel promoted the differentiation of primary human monocytes into pro-inflammatory macrophages with an M1 phenotype and an ability to present antigens to T cells. Monocytes treated with Docetaxel also displayed an elevated secretion of IL-8 and IL-1β, but did not promote generation of monocytic myeloid-derived suppressor cells. In conclusion, Docetaxel appears to have an immune stimulatory effect that would be beneficial for an anti-tumorigenic type of immune response, whereas Paclitaxel seems to have less effect on myeloid cells.

Androgen Receptor and Its Splicing Variant 7 Expression in Peripheral Blood Mononuclear Cells and in Circulating Tumor Cells in Metastatic Castration-Resistant Prostate Cancer

“…Moreover, AR signaling activation has been also related to an increase of RACK1 expression, a scaffold of protein kinase C (PKC) which stabilizes its conformation and promotes the activation of several pathways such as the lipopolysaccharide-induced monocytes/macrophage activation [36]. Taxanes have been also reported as stimulators of the anticancer immune response exerting an activation of macrophage, T-cell, and NK-cell function [37][38][39]. Conversely, anti-hormonal treatment may exert a down-regulation of the PKC signaling molecule RACK1 and a decrease in monocyte activation on human PBMC [36].…”

Intratumoral submicron particle docetaxel inhibits syngeneic Renca renal cancer growth and increases CD4+, CD8+, and Treg levels in peripheral blood

“…Clinical trials are underway to explore the use of IV docetaxel alone or in combination with other agents against other advanced solid tumors and genitourinary cancers, including renal cell carcinoma [8]. Docetaxel stabilizes microtubule polymers, inhibiting mitosis and tumor cell proliferation and impacting inflammation and immunity [9,10]. Significant toxicities, especially neutropenia, are frequently seen in patients treated with IV docetaxel [7].…”

The Potential of Combining Tubulin-Targeting Anticancer Therapeutics and Immune Therapy

“…Thus, it is clear that the contradictory effects of colchicine on inflammation and immune system should be investigated further if we want to utilize a colchicine-immune combinational therapy. Similar to colchicine, docetaxel also appears to promote the differentiation of human monocytes into pro-inflammatory M1 type macrophages, while slightly decreasing the anti-inflammatory M2 macrophages [44]. This is a contrast to paclitaxel, which does not alter the differentiation of M1 or M2 macrophages [44].…”

“…Similar to colchicine, docetaxel also appears to promote the differentiation of human monocytes into pro-inflammatory M1 type macrophages, while slightly decreasing the anti-inflammatory M2 macrophages [44]. This is a contrast to paclitaxel, which does not alter the differentiation of M1 or M2 macrophages [44]. However, both of them do promote the activation of monocytes and macrophages in vitro [44].…”

“…This is a contrast to paclitaxel, which does not alter the differentiation of M1 or M2 macrophages [44]. However, both of them do promote the activation of monocytes and macrophages in vitro [44]. Interestingly, the activation of monocytes by docetaxel may be relevant to its induction of IL-8 and IL-1β.…”