Blockade of B7-H1 or B7-DC induces an anti-tumor effect in a mouse pancreatic cancer model

Abstract

Abstract. The negative signal provided by interactions of programmed death-1 (PD-1) and its ligands, B7-H1 and B7-DC, has been suggested to play an important role in tumor evasion from host immunity. Pancreas cancer patients with B7-H1 expression have a poor prognosis. B7-H1 blocking has been shown to inhibit the development of a subcutaneous tumor from a pancreas cancer cell line. In this study, we investigated the effects of B7-DC as well as B7-H1 blockade in vivo in a murine pancreatic cancer model. Pancreatic cancer cells (Panc02) were inoculated in the pancreas of C57BL/6 mice. Five weeks later, tumor sizes were measured and the mice bearing appropriate size of tumors received the following treatments. Blocking antibodies against B7-H1 or B7-DC (200 μg) were administered 3 times/week for 3 weeks. Cells infiltrating the tumors were characterized by immunohistochemistry. Effects of antibodies on cytokine and FoxP3 expression were examined by quantitative RT-PCR. In vitro cultured Panc02 cells expressed B7-H1 upon IFN-Á stimulation. However, expression of B7-H1 and B7-DC was found mainly on CD45-positive infiltrating cells and rarely on cancer cells in vivo. Treatment with both antibodies significantly decreased tumor growth in vivo. B7-DC blockade decreased the levels of IL-10 and FoxP3, suggesting that regulatory systems are mainly inhibited at the tumor site. B7-H1 blockade increased the levels of IFN-Á and FoxP3. Collectively, blocking of B7-H1 or B7-DC efficiently induced regression of pre-established pancreatic cancers by upregulating IFN-Á production and down-regulating IL-10 production at the tumor site.

Correlation Between PD-L2 Expression and Clinical Outcome in Solid Cancer Patients: A Meta-Analysis

“…In recent years, immune checkpoint inhibitors, particularly those targeting the PD-1 pathway, have become a paradigm-shifting therapy in cancer treatment. Blockade of PD-L2 in a pancreatic murine model also displayed evident anti-tumor effects with decreased tumor outgrowth rates (43). In contrast, a PD-L2 knockout mouse bearing a CT26 tumor exhibited a weakened tumor-specific cytotoxic T lymphocyte response and more rapid tumor growth compared with a WT mouse bearing CT26 (44).…”

Immune checkpoints in targeted-immunotherapy of pancreatic cancer: New hope for clinical development

“…A study was conducted in Panc-02 cells, where they were directly injected into the pancreas. It was shown that blocking antibodies against B7–H1 could suppress tumor growth 179 . Studies in the MiaPaCa-2 and Su86.80 cell lines showed that the anti-inflammatory cytokines such as IL-10 resulted in a modest decrease in mRNA level of PD-L1 in PCa cells.…”

Acquired Resistance to PD-1/PD-L1 Blockade in Lung Cancer: Mechanisms and Patterns of Failure

“…Early experiments showed that in mouse models of myeloma, tumors were found to upregulate surface PD-L1 to reduce T cell effector functions, and the growth of transplanted tumor cells could be reduced by using anti-PD-L1 antibodies [2]. Observations such as these [18][19][20], along with the findings of upregulation of PD-L1 in a variety of different solid tumors [21], led to further research and development of anti-PD-1/PD-L1 antibodies in humans. As of 2020, we now have four FDA-approved anti-PD-1 and anti-PD-L1 therapies for lung cancers alone.…”