Immune suppression/evasion is one of the major impediments to the development of effective immune therapy for cancer. Programmed death-1 receptor (PD-1) is a member of the B7 family that is expressed on activated T cells and is found to play an important role in immune
Lapatinib evasion. On binding its cognate ligands programmed death ligand (PDL)-1 or PDL-2, PD-1 down-regulates signaling by the T-cell receptor (TCR), inducing T-cell anergy and apoptosis and thus leading to immune suppression 1–6. Many human malignancies up-regulate PDL-1, and this up-regulation has been directly correlated with immune suppression and poor prognosis in several types of cancer 4, 7–11. The PD-1/PDL-1 interaction leads to suppression and apoptosis of tumor-infiltrating
effector lymphocytes in the tumor microenvironment 12, 13. Furthermore, PDL-1 was found to be an anti-apoptotic receptor on tumor cells, functioning as an “immune shield” and protecting tumor cells from T-cell cytotoxicity 14–16. More recently, it was found that blocking the PD-1/PDL-1 interaction promotes antigen-specific cytotoxic T lymphocyte (CTL) proliferation by heightening CTL resistance to Treg-cell Gefitinib mw inhibition, and limiting the inhibitory ability of Treg cells 17. Treg cells are inhibitory CD4+ T cells that are increased in cancer patients and can potentially form a barrier to eliciting effective immune response 17–22. Not surprisingly, the inactivation or depletion of Treg cells has been actively pursued, in order to develop more potent anti-tumor immunotherapies. In several studies, antibodies against the CD25 cell surface marker have been used to examine the feasibility of enhancing anti-tumor responses through the inhibition of regulatory cell activity. Depletion of Treg cells by anti-CD25 antibodies has led to enhanced immunity in several tumor models 23–25. One major obstacle Urease for using this approach
is that activated CD4+ and CD8+ T cells also express CD25, and use of anti-CD25 antibodies might also affect these cells. Use of other cell markers, such as CTLA-4, may also be insufficient since it was previously demonstrated that Treg cells from CTLA-4 knockout mice maintain their suppressive function 26, 27. Cyclophosphamide (CPM) has been used as a standard alkylating chemotherapeutic agent against certain solid tumors and lymphomas because of its direct cytotoxic effect and its inhibitory activity against actively dividing cells 28. While high doses of CPM may lead to the depletion of immune cells, low doses of CPM have been shown to enhance immune responses and induce anti-tumor immune-mediated effects by reducing the number and function of Treg cells 27, 29–33. Here, we hypothesize that combining inhibition of Treg cells with strategies that block the PD-1/PDL-1 interaction and vaccine would result in a potent anti-tumor immunotherapeutic strategy.