Adenovirus Improves the Efficacy of Adoptive T-cell Therapy by Recruiting Immune Cells to and Promoting Their Activity at the Tumor

S. Tahtinen, S. Gronberg-Vaha-Koskela, D. Lumen, M. Merisalo-Soikkeli, M. Siurala, A. J. Airaksinen, M. Vaha-Koskela, A. Hemminki
2015 Cancer immunology research  
Despite the rapid progress in the development of novel adoptive T-cell therapies, the clinical benefits in treatment of established tumors have remained modest. Several immune evasion mechanisms hinder T-cell entry into tumors and their activity within the tumor. Of note, oncolytic adenoviruses are intrinsically immunogenic due to inherent pathogen-associated molecular patterns. Here, we studied the capacity of adenovirus to overcome resistance of chicken ovalbumin-expressing B16.OVA murine
more » ... B16.OVA murine melanoma tumors to adoptive ovalbumin-specific CD8 þ T-cell (OT-I) therapy. Following intraperitoneal transfer of polyclonally activated OT-I lymphocytes, control of tumor growth was superior in mice given intratumoral adenovirus compared with control mice, even in the absence of oncolytic virus replication. Preexisting antiviral immunity against serotype 5 did not hinder the therapeutic efficacy of the combination treatment. Intratumoral adenovirus injection was associated with an increase in proinflammatory cytokines, CD45 þ leukocytes, CD8 þ lymphocytes, and F4/80 þ macrophages, suggesting enhanced tumor immunogenicity. The proinflammatory effects of adenovirus on the tumor microenvironment led to expression of costimulatory signals on CD11c þ antigen-presenting cells and subsequent activation of T cells, thus breaking the tumor-induced peripheral tolerance. An increased number of CD8 þ T cells specific for endogenous tumor antigens TRP-2 and gp100 was detected in combination-treated mice, indicating epitope spreading. Moreover, the majority of virus/T-cell-treated mice rejected the challenge of parental B16. F10 tumors, suggesting that systemic antitumor immunity was induced. In summary, we provide proof-of-mechanism data on combining adoptive T-cell therapy and adenovirotherapy for the treatment of cancer. Conception and design: S. T€ ahtinen, A.J. Airaksinen, M. V€ ah€ a-Koskela, A. Hemminki Development of methodology: S. T€ ahtinen, S. Gr€ onberg-V€ ah€ a-Koskela, D. Lumen, M. V€ ah€ a-Koskela Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): S. T€ ahtinen, D. Lumen, M. Siurala, A.J. Airaksinen, M. V€ ah€ a-Koskela Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): S. T€ ahtinen, D. Lumen, A.J. Airaksinen, M. V€ ah€ a-Koskela, A. Hemminki Writing, review, and/or revision of the manuscript: S. T€ ahtinen, M. Siurala, A.J. Airaksinen, M. V€ ah€ a-Koskela, A. Hemminki Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): S. Gr€ onberg-V€ ah€ a-Koskela, D. Lumen, M. Merisalo-Soikkeli, M. V€ ah€ a-Koskela, A. Hemminki Study supervision: M. V€ ah€ a-Koskela, A. Hemminki
doi:10.1158/2326-6066.cir-14-0220-t pmid:25977260 fatcat:n3yl5owq6zgublhnvdv5lkd5ta