Background: Despite the fast growing rate in the development of novel adoptive T-cell therapies, the clinical benefit in established solid tumors has remained modest. Roadblocks to effective immune attack by infiltrating tumor-specific T-cells include several immune evasion mechanisms, which contribute to tumor tolerance. Oncolytic virotherapy on the other hand is the use of cancer cell specific, conditionally replicative viruses in the treatment of cancer. Oncolytic virotherapy has been suggested to enhance epitope spreading by direct oncolysis of tumor cells, leading to enhanced antigen presentation by dendritic cells and increased immunogenicity of the established tumor by providing virus mediated danger signal in the form of pathogen-associated molecular patterns, which are efficiently recognized by the immune system. Here, we studied the combination of these two established forms of immunotherapy in a highly resistant and poorly immunogenic B16.OVA mouse melanoma model.
Methods: Immunocompetent B16.OVA bearing C57BL/6 female mice were adoptively transferred with CD8a+ enriched, OVA-specific OT-I lymphocytes and treated with intratumoral injections 5/3-fiber chimeric adenovirus (diluted in saline) on six consecutive days. Tumor growth of mice was monitored every 2-3 days by using electronic calipers. Mice were sacrificed on day 14 post-transfer and immune composition of harvested tumors was analyzed by flow cytometry.
Results: Following adoptive transfer of OT-I lymphocytes, superior tumor growth control was observed in adenovirus-treated mice compared to control mice, even in the absence of active oncolysis. Significant increase in infiltration of CD45+ leukocytes, CD8+ lymphocytes and F4/80+ macrophages was seen adenovirus-treated tumors suggesting enhanced tumor immunogenicity. Pro-inflammatory tumor microenvironment mediated by adenovirus infection led to expression of co-stimulatory signals on CD11c+ antigen presenting cells and subsequent activation of T-cells, thus breaking the tumor-induced peripheral tolerance of T-cells. Moreover, epitope spreading in the form of endogenous anti-melanoma T-cells was detected in the combination treated mice indicating that the dual approach can lead to systemic anti-tumor immunity.
Conclusions: Treatment with adenovirus can overcome resistance of B16.OVA murine melanoma tumors to T-cell therapy by recruitment and stimulation of tumor-infiltrating immune cells, thus improving the efficacy of adoptive T-cell therapy in solid tumors.
Citation Format: Siri Tähtinen, Susanna Grönberg-Vähä-Koskela, Dave Lumen, Mikko Siurala, Anu J. Airaksinen, Markus Vähä-Koskela, Akseli Hemminki. Combination of adenovirus and adoptive T-cell therapy breaks tumor tolerance by recruiting immune cells to and promoting their activity in the tumor. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B21.