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

Abstract

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 melanoma tumors to adoptive ovalbumin-specific CD8(+) 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(+) leukocytes, CD8(+) lymphocytes, and F4/80(+) macrophages, suggesting enhanced tumor immunogenicity. The proinflammatory effects of adenovirus on the tumor microenvironment led to expression of costimulatory signals on CD11c(+) antigen-presenting cells and subsequent activation of T cells, thus breaking the tumor-induced peripheral tolerance. An increased number of CD8(+) 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.

• Authors: Siri Tähtinen, Susanna Grönberg-Vähä-Koskela, Dave Lumen, Maiju Merisalo-Soikkeli, Mikko Siurala, Anu J Airaksinen, Markus Vähä-Koskela, Akseli Hemminki
• Journal: Cancer immunology research (Cancer Immunol Res) Vol. 3 Issue 8 Pg. 915-25 (Aug 2015) ISSN: 2326-6074 [Electronic] United States
• PMID: 25977260 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Antigens, Neoplasm
• Biomarkers

Topics

• Adenoviridae (immunology)
• Adenoviridae Infections (immunology)
• Adoptive Transfer
• Animals
• Antigen Presentation (immunology)
• Antigens, Neoplasm (immunology)
• Biomarkers
• Clonal Anergy
• Cross-Priming (immunology)
• Disease Models, Animal
• Humans
• Immunomodulation
• Lymphocyte Activation (immunology)
• Melanoma, Experimental
• Mice
• Neoplasms (immunology, therapy)
• Oncolytic Viruses (immunology)
• T-Lymphocytes (immunology, metabolism)