Gemcitabine enhances the efficacy of reovirus-based oncotherapy through anti-tumour immunological mechanisms

Abstract

Background:Reovirus preferentially infects and kills cancer cells and is currently undergoing clinical trials internationally. While oncolysis is the primary mode of tumour elimination, increasing evidence illustrates that reovirus additionally stimulates anti-tumour immunity with a capacity to target existing and possibly relapsing cancer cells. These virus-induced anti-tumour immune activities largely determine the efficacy of oncotherapy. On the other hand, anti-viral immune responses can negatively affect oncotherapy. Hence, the strategic management of anti-tumour and anti-viral immune responses through complementary therapeutics is crucial to achieve the maximum anti-cancer benefits of oncotherapy.Methods:Intra-peritoneal injection of mouse ovarian surface epithelial cells (ID8 cells) into wild-type C57BL/6 mice was treated with a therapeutic regimen of reovirus and/or gemcitabine and then analysed for prolonged survival, disease pathology, and various immunological parameters. Furthermore, in vitro analyses were conducted to assess apoptosis, viral spread, and viral production during reovirus and/or gemcitabine treatment.Results:We demonstrate that reovirus and gemcitabine combination treatment postpones peritoneal carcinomatosis development and prolongs the survival of cancer-bearing hosts. Importantly, these anti-cancer benefits are generated through various immunological mechanisms, including: (1) inhibition of myeloid-derived suppressor cells recruitment to the tumour microenvironment, (2) downmodulation of pro-MDSC factors, and (3) accelerated development of anti-tumour T-cell responses.Conclusion:The complementation of reovirus with gemcitabine further potentiates virus-initiated anti-cancer immunity and enhances the efficacy of oncotherapy. In the context of ongoing clinical trials, our findings represent clinically relevant information capable of enhancing cancer outcomes.

Newly Recruited CD11b+, GR-1+, Ly6Chigh Myeloid Cells Augment Tumor-Associated Immunosuppression Immediately following the Therapeutic Administration of Oncolytic Reovirus

“…Isolation of lymphocyte, BM hematopoietic progenitor cells, MDSCs, and cell-free ascitic fluid Splenocytes containing lymphocytes and BM hematopoietic progenitor cells were isolated as previously described (17). Ascitic fluid from the peritoneal cavity of the PC-bearing mice was centrifuged to pellet constituent cells.…”

“…These reovirus-induced antitumor immunotherapeutic activities target existing cancer cells and can protect the host against subsequent tumor relapse even after discontinuation of the therapy (15). Following its therapeutic administration, reovirus invokes a sequence of immunological events that ultimately overturns numerous tumor-associated immune evasion mechanisms and facilitates the development of antitumor innate and adaptive immune responses (15)(16)(17)(18)(19)(20)(21). Thus, comprehensive characterization and subsequent therapeutic management of the virus-induced immunological events are absolutely necessary to harness the beneficial effects of reovirus-driven anticancer therapy.…”

“…therapeutic injections of reovirus drive the accumulation of CD11b + , Gr-1 + myeloid cells in the tumor microenvironment of hosts with peritoneal carcinomatosis (PC) (17,18). However, the detailed characteristics, the pathophysiological significance of such virus-driven MDSCs, and the possible subpopulations in the context of tumor microenvironment are at present unknown.…”

All that glitters is not gold: the need to consider desirable and undesirable immune aspects of oncolytic virus therapy

“…10 It therefore seems clear that only through the strategic management of such immunosuppressive entities can we promote the optimum efficacy for OV-based oncotherapies (summarized in Fig. 1).…”

Strategic Combinations: The Future of Oncolytic Virotherapy with Reovirus

“…The combination of reovirus and gemcitabine, a deoxycytidine analog, significantly increased the survival of ID8 tumor-bearing C57BL/6 mice compared with either agent as monotherapy (48). Gemcitabine is an FDA-approved antiovarian cancer chemotherapeutic known to inhibit myeloid-derived suppressor cells (MDSC).…”