Natural Products Induce Different Anti-Tumor Immune Responses in Murine Models of 4T1 Mammary Carcinoma and B16-F10 Melanoma

Abstract

Natural products obtained from Petiveria alliacea (Anamu-SC) and Caesalpinia spinosa (P2Et) have been used for cancer treatment, but the mechanisms by which they exert their antitumor activity appear to be different. In the present work, we show that the Anamu-SC extract reduces tumor growth in the 4T1 murine mammary carcinoma model but not in the B16-F10 melanoma model, unlike the standardized P2Et extract. Both extracts decreased the levels of interleukin-10 (IL-10) in the B16-F10 model, but only P2Et increased the levels of tumor necrosis factor alpha (TNFα) and interferon gamma (IFNγ). Likewise, co-treatment of P2Et and doxorubicin (Dox) significantly reduced tumor size by 70% compared to the control group, but co-treatment of Anamu-SC with Dox had no additive effect. Analysis of intratumoral immune infiltrates showed that Anamu-SC decreased CD4+ T cell frequency more than P2Et but increased CD8+ T cell frequency more significantly. Both extracts reduced intratumoral monocytic myeloid-derived suppressor-like cell (M-MDSC-LC) migration, but the effect was lost when co-treated with doxorubicin. The use of P2Et alone or in co-treatment with Anamu-SC reduced the frequency of regulatory T cells and increased the CD8+/Treg ratio. In addition, Anamu-SC reduced glucose consumption in tumor cells, but this apparently has no effect on IFNγ- and TNFα-producing T cells, although it did reduce the frequency of IL-2-producing T cells. The efficacy of these herbal preparations is increasingly clear, as is the specificity conditioned by tumor heterogeneity as well as the different chemical complexity of each preparation. Although these results contribute to the understanding of specificity and its future benefits, they also underline the fact that the development of each of these standardized extracts called polymolecular drugs must follow a rigorous path to elucidate their biological activity.