Translational nanomedicine potentiates immunotherapy in sarcoma by normalizing the microenvironment.

Nanocarrier-based chemo-immunotherapy has succeeded in clinical trials and understanding its effect on the tumor microenvironment could facilitate development of strategies to increase efficacy of these regimens further. NC-6300 (epirubicin micelle) demonstrates anti-tumor activity in sarcoma patients, but whether it is combinable with immune checkpoint inhibition is unclear. Here, we tested NC-6300 combined with anti-PD-L1 antibody in mouse models of osteosarcoma and fibrosarcoma. We found that sarcoma responds to NC-6300 in a dose-dependent manner, while anti-PD-L1 efficacy is potentiated even at a dose of NC-6300 less than 10% of the maximum tolerated dose. Furthermore, NC-6300 is more effective than the maximum tolerated dose of doxorubicin in increasing the tumor growth delay induced by anti-PD-L1 antibody. We investigated the mechanism of action of this combination. NC-6300 induces immunogenic cell death and its effect on the efficacy of anti-PD-L1 antibody is dependent on T cells. Also, NC-6300 normalized the tumor microenvironment (i.e., ameliorated pathophysiology towards normal phenotype) as evidenced through increased blood vessel maturity and reduced fibrosis. As a result, the combination with anti-PD-L1 antibody increased the intratumor density and proliferation of T cells. In conclusion, NC-6300 potentiates immune checkpoint inhibition in sarcoma, and normalization of the tumor microenvironment should be investigated when developing nanocarrier-based chemo-immunotherapy regimens.

Inhibition of human breast cancer growth by GCP (genistein combined polysaccharide) in xenogeneic athymic mice: involvement of genistein biotransformation by beta-glucuronidase from tumor tissues.

The role of beta-glucuronidase in genistein biotransformation was investigated in a human breast cancer MDA-MB-231 xenogeneic athymic mouse model. Genistein combined polysaccharide (GCP), a genistein aglycone rich functional food supplement was used in these experiments. Tumor-bearing mice were subjected to oral administration of GCP for 28 days. GCP treatment significantly inhibited tumor growth. Induction of apoptosis by GCP treatment was related to activation of cleavage of poly(ADP-ribose)polymerase, induction of the p21 protein expression and reduction of cyclin B1 expression in the tumor tissues. Genistein exists as a glucuronide conjugate in normal organ tissues, and the conjugated genistein lacks the physiological activity of the aglycone. Tumor tissues contain large amounts of beta-glucuronidase, the enzyme that converts the genistein beta-glucuronide conjugate into genistein aglycone. The resulting genistein aglycone exerts its chemopreventive activities, including the induction of apoptosis in tumor tissues, and, finally, leads to tumor growth inhibition.

The role of beta-glucuronidase in induction of apoptosis by genistein combined polysaccharide (GCP) in xenogeneic mice bearing human mammary cancer cells.

In order to reveal the mechanisms underlying genistein combined polysaccharide (GCP) inhibition of tumor proliferation, we investigated the effects of GCP on the growth of human breast cancer cells transplanted to athymic nude mice. We further investigated the metabolism of genistein and its association with the beta-glucuronidase activity in tumor and normal tissues.