Activated dendritic cells delivered in tissue compatible biomatrices induce in-situ anti-tumor CTL responses leading to tumor regression
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Vivek Verma1,9,10, Young Kim2, Min-Cheol Lee2, Jae-Tae Lee3, Sunghoon Cho4, In-Kyu Park5, Jung Joon Min6, Je Jung Lee1,7, Shee Eun Lee1,8, Joon Haeng Rhee1,9
1Clinical Vaccine R&D Center, Chonnam National University Medical School, Gwangju, South Korea
2Department of Pathology, Chonnam National University Medical School, Gwangju, South Korea
3Department of Nuclear Medicine, Kyungpook National University School of Medicine, Daegu, South Korea
4School of Mechanical Systems Engineering, Chonnam National University, Gwangju, South Korea
5Department of Biomedical Science, Chonnam National University Medical School, Gwangju, South Korea
6Department of Nuclear Medicine, Chonnam National University Medical School, Gwangju, South Korea
7Research Center for Cancer Immunotherapy, Hwasun Hospital, Chonnam National University, Hwasun, South Korea
8Department of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National University, Gwangju, South Korea
9Department of Microbiology, Chonnam National University Medical School, Gwangju, South Korea
10Present address: GRU Cancer Center, GRU, Augusta, GA, USA
Joon Haeng Rhee, email: [email protected]
Keywords: dendritic cells, tumor, immunotherapy, biomatrices
Received: December 29, 2015 Accepted: April 25, 2016 Published: May 20, 2016
Dendritic cell (DC) based anti-cancer immunotherapy is well tolerated in patients with advanced cancers. However, the clinical responses seen after adoptive DC therapy have been suboptimal. Several factors including scarce DC numbers in tumors and immunosuppressive tumor microenvironments contribute to the inefficacy of DCs as cellular vaccines. Hence DC based vaccines can benefit from novel methods of cell delivery that would prevent the direct exposure of immune cells to suppressive tumor microenvironments. Here we evaluated the ability of DCs harbored in biocompatible scaffolds (referred to as biomatrix entrapped DCs; beDCs) in activating specific anti-tumor immune responses against primary and post-surgery secondary tumors. Using a preclinical cervical cancer and a melanoma model in mice, we show that single treatment of primary and post-surgery secondary tumors using beDCs resulted in significant tumor growth retardation while multiple inoculations were required to achieve a significant anti-tumor effect when DCs were given in free form. Additionally, we found that, compared to the tumor specific E6/E7 peptide vaccine, total tumor lysate induced higher expression of CD80 and CD40 on DCs that induced increased levels of IFNγ production upon interaction with host lymphocytes. Remarkably, a strong immunocyte infiltration into the host-implanted DC-scaffold was observed. Importantly, the host-implanted beDCs induced the anti-tumor immune responses in the absence of any stromal cell support, and the biomatrix structure was eventually absorbed into the surrounding host tissue. Collectively, these data indicate that the scaffold-based DC delivery may provide an efficient and safe way of delivering cell-based vaccines for treatment of primary and post-surgery secondary tumors.
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