Enhanced tumor eradication by combining CTLA-4 or PD-1 blockade with CpG therapy
2010 (English)In: Journal of immunotherapy (1997), ISSN 1524-9557, E-ISSN 1537-4513, Vol. 33, no 3, 225-235 p.Article in journal (Refereed) Published
Tumor immunotherapy aims to break effector T cell anergy and to block suppressive cell types and ligands allowing effector cells to exert tumor eradication. Previous reports demonstrate that cytotoxic T lymphocyte antigen-4 (CTLA-4)-blocking antibodies promote T cell activation and render T effector cells resistant to T regulatory cells (Tregs) whereas programmed death receptor-1 (PD-1)/ PD-L1 blockade results in loss of peripheral tolerance. Herein, we explored single or combined antibody blockade of CTLA-4 and PD-1 alone or combined with the TLR agonists CpG or bacillus Calmette-Guerin (BCG) for treatment of murine experimental bladder cancer. In therapeutic studies, tumors were rejected by anti-CTLA4 (aCTLA4) while aPD-1 suppressed tumor growth. The combination had no additive effect compared with aCTLA-4 alone. However, elevated levels of circulating CD107a expressing CD8+ T cells were found in the aCTLA-4 plus aPD-1 group. In addition, levels of antinuclear antibodies (ANA) correlated inversely with tumor size. Next, we combined CpG or BCG with aCTLA-4, aPD-1 or aPD-L1 and found that CpG in combination with aCTLA-4 or aPD-1 increased the survival of mice, with aPD-1 plus CpG being superior to either agent alone. CpG plus aCTLA-4 or aPD-1 increased the numbers of circulating tumor-specific CD107a expressing CD8+ T cells as well as activated (CD25+ FoxP3-) CD4+ splenocytes. Further, we investigated the numbers of Tregs in the tumor area of treated animals and detected decreased levels after aCTLA-4 or aPD-1 plus CpG therapy. Thus, the combination of CpG with CTLA-4 or PD-1 blockade improved long-term survival and led to increased levels of tumor-reactive T cells and reduced numbers of Tregs at the tumor site.
Place, publisher, year, edition, pages
2010. Vol. 33, no 3, 225-235 p.
CTLA-4, PD-1, CpG, BCG, bladder cancer, immunotherapy, combination therapies, MB49, TLR-9
Immunology in the medical area
IdentifiersURN: urn:nbn:se:uu:diva-110726DOI: 10.1097/CJI.0b013e3181c01fcbISI: 000276037500001PubMedID: 20445343OAI: oai:DiVA.org:uu-110726DiVA: diva2:278085