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 to control mice, even in the absence of oncolytic virus replication. Pre-existing anti-viral immunity against serotype 5 did not hinder the therapeutic efficacy of the combination treatment. Intratumoral adenovirus injection was associated with an increase in pro-inflammatory cytokines, CD45+ leukocytes, CD8+ lymphocytes and F4/80+ macrophages, suggesting enhanced tumor immunogenicity. The pro-inflammatory effects of adenovirus on the tumor microenvironment 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. 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, majority of virus/T-cell -treated mice rejected the challenge of parental B16.F10 tumors, suggesting that systemic anti-tumor immunity was induced. In summary, we provide proof-of-mechanism data on combining adoptive T-cell therapy and adenovirotherapy for the treatment of cancer.
- Received November 22, 2014.
- Revision received April 16, 2015.
- Accepted May 7, 2015.
- Copyright © 2015, American Association for Cancer Research.