Antitumor properties of triptolide: phenotype regulation of macrophage differentiation

Abstract

Tumor-associated macrophages (TAMs), which generally exhibit an M2-like phenotype, play a critical role in tumor development. Triptolide exerts a unique bioactive spectrum of anticancer activities. The aim of this study was to determine whether triptolide has any effect on the activation of TAMs and the production of tumor-promoting mediators. ICR-1 mice with azoxymethane/dextran sulfate sodium (AOM/DSS)-induced colon tumors and BALB/c mice co-inoculated with 4T1 cells and M2-polarized RAW264.7 cells were used to examine whether the inhibitory effect of triptolide on tumor progression was mediated by the targeting of TAMs. Real-time PCR, Western blot, immunofluorescence staining, and flow cytometry assays were performed to determine the expression of cell surface markers and cytokine production. The results showed that triptolide inhibited macrophage differentiation toward the M2 phenotype and abolished M2 macrophage-mediated tumor progression. Furthermore, triptolide inhibited the expression of M2 markers, such as CD206, Arginase 1, and CD204, and inhibited the secretion of anti-inflammatory cytokines. Thus our study indicated that triptolide selectively inhibited the functions of M2-polarized macrophages and TAMs, and this inhibitory effect of triptolide on TAM viability, differentiation, and cytokine production might elucidate the major mechanisms underlying its antitumor activity. Our findings provide important information for the potential clinical application of triptolide in cancer therapy.

Tumor-specific T cells support chemokine-driven spatial organization of intratumoral immune microaggregates needed for long survival

“…The presence of these immune suppressive cells [52][53][54] and the increased expression of the immune suppressive cytokine IL-11, known to suppress the attraction and functionality of tumor-reactive CD4 + T cells, 27 potentially explain why tumor-specific T cells were not detected in these tumors. It also provides a rational foundation for combinations of T cell-stimulating agents 6 55 56 with strategies focusing on the identified resistance mechanisms, for example, cotargeting M2-like macrophages, 57 TGF-β, 58 and/or angiogenesis. 59 In conclusion, the blueprint of a productive TIME comprises the local production of chemokines that not only attract tumor-reactive CD4 + and CD8 + T cells as well as DCs, but also organize them into small aggregates within the tumor cell beds where most likely the DCs gobble up antigens from dying tumor cells and stimulate the T cells to exercise their effector function and to amplify the immune response.…”

“…The presence of these immune suppressive cells 52–54 and the increased expression of the immune suppressive cytokine IL-11 , known to suppress the attraction and functionality of tumor-reactive CD4 + T cells, 27 potentially explain why tumor-specific T cells were not detected in these tumors. It also provides a rational foundation for combinations of T cell-stimulating agents 6 55 56 with strategies focusing on the identified resistance mechanisms, for example, cotargeting M2-like macrophages, 57 TGF-β, 58 and/or angiogenesis. 59 …”

Helicobacter pylori infection reduces TAMs infiltration in a mouse model of AOM/DSS induced colitis-associated cancer

“…In an AOM/DSS-induced CAC mouse model, the percentages of CD68 + macrophages and CD206 + M2 macrophages increased in tumors, accompanied with the up-regulated expression of TNF-α, IL-1β, IL-6 [24]. Studies revealed that anti-tumor drugs inhibited the M2-associated genes, such as CD206, Arginase 1, CD204 and MMP2 in AOM/DSS mouse models [25,26]. The inflammatory cytokines, including TNF-α, IL-1β and IL-6, were also suppressed and the percentages of macrophages were decreased, after using a kind of anti-ulcerative colitis medicine in CAC [27].…”

Impact of TCM on Tumor-Infiltrating Myeloid Precursors in the Tumor Microenvironment

“…In the 4T1 breast cancer mouse model, triptolide (TR), as one diterpenoid epoxide produced by Tripterygium wilfordii Hook. f (one TCM herb), was found to inhibit the expression of CD206, arginase 1, and CD204, and inhibit the secretion of anti-inflammatory cytokines, further inducing the decreased number of tumor-related M2 polarized macrophages to block tumor angiogenesis ( Li et al, 2020 ) ( Table 4 ).…”