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

Abstract

Tumor-associated immunosuppression aids cancer cells to escape immune-mediated attack and subsequent elimination. Recently, however, many oncolytic viruses, including reovirus, have been reported to overturn such immunosuppression and promote the development of a clinically desired antitumor immunity, which is known to promote favorable patient outcomes. Contrary to this existing paradigm, in this article we demonstrate that reovirus augments tumor-associated immunosuppression immediately following its therapeutic administration. Our data show that reovirus induces preferential differentiation of highly suppressive CD11b+, Gr-1+, Ly6Chigh myeloid cells from bone marrow hematopoietic progenitor cells. Furthermore, reovirus administration in tumor-bearing hosts drives time-dependent recruitment of CD11b+, Gr-1+, Ly6Chigh myeloid cells in the tumor milieu, which is further supported by virus-induced increased expression of numerous immune factors involved in myeloid-derived suppressor cell survival and trafficking. Most importantly, CD11b+, Gr-1+, Ly6Chigh myeloid cells specifically potentiate the suppression of T cell proliferation and are associated with the absence of IFN-γ response in the tumor microenvironment early during oncotherapy. Considering that the qualitative traits of a specific antitumor immunity are largely dictated by the immunological events that precede its development, our findings are of critical importance and must be considered while devising complementary interventions aimed at promoting the optimum efficacy of oncolytic virus–based anticancer immunotherapies.

Repurposing Sunitinib with Oncolytic Reovirus as a Novel Immunotherapeutic Strategy for Renal Cell Carcinoma

“…Given this, mechanistic investigations were focused on correlating MDSC and Treg levels with tumor specific CD8 + splenocyte IFN-γ production between monoand combination-therapy groups in vivo. Consistent with an inflammatory cell death, reovirus monotherapy administration induced a marked rise in both immune stimulatory (CD8 + and CD4 + lymphocytes) and suppressor (MDSC and Treg) populations within the spleen and tumor, similar to recent reports in the IP8 ovarian peritoneal carcinomatosis model [33] ( Figure. 4A-F).…”

“…Oncolysis of human RCC cell lines was seen within 48 hours of infection with all ED 50 values being less than 40 MOI, which is comparable to that seen with other solid malignancies [18,[30][31][32]. Notably, the RENCA cell line demonstrated significantly greater in vitro sensitivity relative to human RCC cells, consistent with previous reports highlighting increased murine cell line sensitivity to reovirus [33]. While the precise mechanism for the enhanced sensitivity remains unknown, this observation suggested a direct oncolytic in vivo response could be achieved.…”

The Continued Promise and Many Disappointments of Oncolytic Virotherapy in Gastrointestinal Malignancies

“…Interestingly, increased levels in immunomodulating biomarkers (including Interleukin (IL)-6, Vascular Endothelial Growth Factor (VEGF), and regulatory T cells) were seen in patients that received Reolysin. These results are consistent with preclinical studies that suggest Reolysin may promote and enhance immune suppression in a pre-existing immunosuppressive environment that is seen in pancreatic adenocarcinoma [32]. A second single arm phase II study evaluated the combination of Reolysin with gemcitabine in treatment-naïve patients with advanced pancreatic adenocarcinoma.…”

Randomized Phase 2 Trial of the Oncolytic Virus Pelareorep (Reolysin) in Upfront Treatment of Metastatic Pancreatic Adenocarcinoma

“…Some studies suggest that it may potentiate the host antitumor immune response, [10][11][12][13][14] while others show that it can further exacerbate immunosuppressive features of advanced cancer. 15 Thus, investigating immune biomarkers in the context of a wellcontrolled clinical trial is of importance for determining whether it may complement emerging immunotherapeutic approaches for metastatic disease.…”