Peritumoral CpG DNA Elicits a Coordinated Response of CD8 T Cells and Innate Effectors to Cure Established Tumors in a Murine Colon Carcinoma Model

Abstract

The immune system of vertebrates is able to detect bacterial DNA based on the presence of unmethylated CpG motifs. We examined the therapeutic potential of oligodeoxynucleotides with CpG motifs (CpG ODN) in a colon carcinoma model in BALB/c mice. Tumors were induced by s.c. injection of syngeneic C26 cells or Renca kidney cancer cells as a control. Injection of CpG ODN alone or in combination with irradiated tumor cells did not protect mice against subsequent tumor challenge. In contrast, weekly injections of CpG ODN into the margin of already established tumors resulted in regression of tumors and complete cure of mice. The injection site was critical, since injection of CpG ODN at distant sites was not effective. Mice with two bilateral C26 tumors rejected both tumors upon peritumoral injection of one tumor, indicating the development of a systemic immune response. The tumor specificity of the immune response was demonstrated in mice bearing a C26 tumor and a Renca tumor at the same time. Mice that rejected a tumor upon peritumoral CpG treatment remained tumor free and were protected against rechallenge with the same tumor cells, but not with the other tumor, demonstrating long term memory. Tumor-specific CD8 T cells as well as innate effector cells contributed to the antitumor activity of treatment. In conclusion, peritumoral CpG ODN monotherapy elicits a strong CD8 T cell response and innate effector mechanisms that seem to act in concert to overcome unresponsiveness of the immune system toward a growing tumor.

TLR Ligands in the Local Treatment of Established Intracerebral Murine Gliomas

“…Therefore, a key issue to successfully treat gliomas is to attenuate Treg-mediated suppression and, concomitantly, to stimulate tumor-reactive immune-effector cells. As activation of the immune system by local TLR-stimulation has been shown to reverse the immunosuppressive tumor environment in several cancer models (23,29,32), this study was designed to explore the potency of various TLR ligands to induce immunity against established intracerebral murine GL261 gliomas in vivo and to determine their direct impact on these tumor cells in vitro.…”

In vivo Colocalization of Antigen and CpG within Dendritic Cells Is Associated with the Efficacy of Cancer Immunotherapy

“…Importantly, mature DCs acquire the unique ability to present captured antigens on MHC class I molecules, a process known as cross-presentation (7), which is crucial for efficient priming of tumor-specific CTLs (8,9). As such, CpG administration has been reported to prevent tumor outgrowth in a prophylactic setting and could also eradicate established tumors in mice (10,11).…”

MUC1-specific immune therapy generates a strong anti-tumor response in a MUC1-tolerant colon cancer model

“…The net effect of TLR9 activation is to induce Th1 biased cellular and humoral effector functions with strong CTL generation [33]. In murine models of cancer and in phase I/II clinical trials in patients with metastatic melanoma and non-small cell lung cancer, CpG ODN has improved tumor responses to conventional therapies such as chemotherapy, radiotherapy, and immunotherapy [34][35][36][37][38][39][40][41]. GM-CSF is a commercially available cytokine currently used in patients undergoing chemotherapy to shorten the duration of post-chemotherapy neutropenia.…”