Arsenic trioxide synergizes with B7H3‐mediated immunotherapy to eradicate hepatocellular carcinomas

Abstract

Arsenic trioxide (As 2 O 3 ), a valuable anticancer drug for the treatment of acute promyelocytic leukemia, may also have therapeutic potential for the treatment of solid tumors. However, its therapeutic efficacy against solid tumors is lacking even at high dosages. Other therapeutic strategies are required to enhance the efficacy of As 2 O 3 against solid tumors such as hepatocellular carcinoma (HCC), which is refractory to chemotherapy. B7H3, a new member of the B7 family, has been shown to induce antitumor immunity. Intratumoral injection of B7H3 plasmids eradicates small EL-4 lymphomas, but monotherapy is ineffective against large tumors. Here we investigated whether As 2 O 3 would synergize with B7H3 immunotherapy to combat HCC. Large subcutaneous H22 HCCs (0.7-0.8 cm in diameter) established in BALB/c mice were rapidly and completely eradicated when intratumoral administration of As 2 O 3 was preceded by in situ gene transfer of B7H3. In contrast, neither As 2 O 3 nor B7H3 monotherapy was effective. The antitumor activity of As 2 O 3 was attributed to increased tumor-cell apoptosis, perhaps as a result of direct cytotoxicity as well as decreased tumor angiogenesis. Combination therapy generated potent systemic antitumor immunity mediated by CD81 and NK cells that was effective in combating a systemic challenge of 1 3 10 7 parental H22 cells. It led to the simultaneous and complete regression of multiple distant tumor nodules, concomitant with increased levels of serum IFN-c and cytotoxic T lymphocyte (CTL) activity. In conclusion, combining B7H3-mediated immunotherapy with As 2 O 3 warrants investigation as a therapeutic strategy to combat HCC, and other malignancies. ' 2005 Wiley-Liss, Inc.

Antiangiogenic therapy enhances the efficacy of transcatheter arterial embolization for hepatocellular carcinomas

“…14,18,19 Briefly, frozen sections were fixed with acetone, blocked with 2% BSA and incubated overnight with primary antibodies. They were subsequently incubated with appropriate secondary antibodies using the SABC kit (Boster Biological Technology, Wuhan, China) and developed with Sigma FAST DAB (3,3 0 -diaminobenzidine tetrahydrochloride) and CoCl 2 enhancer tablets (Sigma).…”

“…14,18,19 Briefly, frozen sections were immunostained with an anti-CD31 Ab, as described above. Stained vessels were counted in 5 blindly chosen random fields, and the mean of the highest 3 counts was recorded.…”

The contrasting role of B7-H3

“…CD4 T cells are not required for the induction of CD8 CTL for tumor immunity because depletion of CD4 T cells did not diminish the resistance of mice to the B7-H3-transfected P815 tumor. In a hepatocellular carcinoma model, intratumoral administration of a B7-H3-expressing plasmid and arsenic trioxide synergized to completely eradicate an established tumor (15), whereas neither arsenic trioxide nor B7-H3 monotherapy was effective. In these mouse cancer models, it seems that tumor-associated B7-H3 preferentially regulates CD4-independent induction of CD8 CTL responses.…”

“…In addition, B7-H3 transiently transfected melanoma cells can enhance induction of human primary CD8 cytotoxic T cells (CTLs). Subsequently, in several mouse cancer models it has been shown that ectopic expression of B7-H3 leads to activation of tumor-specific CTLs that are able to slow tumor growth or even completely eradicate tumors (14)(15)(16). Mice with a B7-H3-transfected colon cell line had significantly prolonged survival times (16).…”

Clinical importance of B7-H3 expression in human pancreatic cancer

“…B7-H3 expression has been identified in several tumour cell lines and in actual human tumour specimens, including gastric cancer, non-small-cell lung cancer, and prostate cancer Wu et al, 2006;Roth et al, 2007;Zang et al, 2007). Several murine studies have shown that introduction of B7-H3 in tumour cells and tissues by various methods activates tumour-specific immunocompetent cells and promotes anti-tumour response, thereby leading to rapid tumour regression, reduction of metastasis, and prolongation of animal survival (Sun et al, 2003;Luo et al, 2004Luo et al, , 2006Lupu et al, 2006Lupu et al, , 2007. In addition, high intra-tumour B7-H3 expression was shown to correlate with better prognosis in gastric cancer (Wu et al, 2006).…”