Antitumor effects of anti-CD40/CpG immunotherapy combined with gemcitabine or 5-fluorouracil chemotherapy in the B16 melanoma model

Abstract

Our previous studies demonstrated that anti-CD40 mAb (anti-CD40) can synergize with CpG oligodeoxynucleotides (CpG) to mediate antitumor effects by activating myeloid cells, such as macrophages in tumor-bearing mice. Separate teams have shown that chemotherapy with gemcitabine (GEM) or 5-fluorouracil (5-FU) can reduce tumor-induced myeloid-derived suppressor cells (MDSC) in mice. In this study we asked if the same chemotherapy regimens with GEM or 5-FU will enhance the antitumor effect of anti-CD40 and CpG. Using the model of B16 melanoma growing intraperitoneally in syngeneic C57BL/6 mice, we show that these GEM or 5-FU treatment regimens reduced MDSC in the peritoneal cavity of tumor-bearing mice. Treatment of mice with GEM or 5-FU did not significantly affect the antitumor function of macrophages as assessed in vitro. In vivo, treatment with these GEM or 5-FU regimens followed by anti-CD40/CpG resulted in antitumor effects similar to those of anti-CD40/CpG in the absence of GEM or 5-FU. Likewise, reduction of MDSC by in vivo anti-Gr-1 mAb treatment did not significantly affect anti-CD40/CpG antitumor responses. Together, the results show that the GEM or 5-FU chemotherapy regimens did not substantially affect the antitumor effects induced by anti-CD40/CpG immunotherapy.

A polyethylenimine-modified carboxyl-poly(styrene/acrylamide) copolymer nanosphere for co-delivering of CpG and TGF-β receptor I inhibitor with remarkable additive tumor regression effect against liver cancer in mice

“…29 Sera were collected and stored at −20°C in 100 μL aliquots. Spleen cells were harvested and rinsed in PBS for fluorescence activating cell sorter analysis.…”

Exploiting natural anti-tumor immunity for metastatic renal cell carcinoma

“…Such chemotherapies as Gemcitabine and 5-Fluoruricil selectively deplete MDSC. 130,143 Small molecule inhibitors for the treatment of RCC, Sorafenib and Sunitnib, have the ability to decrease the suppressive capacity of MDSC in patients. 64,65 These agents are capable of alleviating immune suppression through altering the MDSC populations, but they possess off target effects and toxicities that can have negative effects on subsequent immune responses.…”

Enhancing the anticancer effects of 5-fluorouracil: Current challenges and future perspectives

“…[23] We searched for the mechanism accounting for the activity of 5-FU on MDSCs and found that 5-FU directly triggered MDSC cell death in vitro and in vivo. By testing the presence of activated caspases in 5-FU-treated MDSC murine cell lines, we found that 5-FU drove MDSC apoptosis in vitro, as illustrated by the presence of activated caspases 3 and 7 in 5-FU-treated MDSCs.…”

“…[22] These findings were recently confirmed by Qu et al, who reported using a mouse model of B16 melanoma cancer cells growing intraperitoneally that Gem or 5-FU decreased MDSC numbers in the peritoneal cavity of tumor-bearing mice without altering the anticancer functions of mouse macrophages. [23] We searched for the mechanism accounting for the activity of 5-FU on MDSCs and found that 5-FU directly triggered MDSC cell death in vitro and in vivo. By testing the presence of activated caspases in 5-FU-treated MDSC murine cell lines, we found that 5-FU drove MDSC apoptosis in vitro, as illustrated by the presence of activated caspases 3 and 7 in 5-FU-treated MDSCs.…”