Type 1 Immune Mechanisms Driven by the Response to Infection with Attenuated Rabies Virus Result in Changes in the Immune Bias of the Tumor Microenvironment and Necrosis of Mouse GL261 Brain Tumors

Abstract

Immunotherapeutic strategies for malignant glioma have to overcome the immunomodulatory activities of M2 monocytes that appear in the circulation and as tumor associated macrophages (TAM). M2 cell products contribute to the growth-promoting attributes of the tumor microenvironment (TME) and bias immunity towards type 2, away from the type 1 mechanisms with anti-tumor properties. To drive type 1 immunity in CNS tissues we infected GL261 tumor-bearing mice with attenuated rabies virus (RABV). These neurotropic viruses spread to CNS tissues trans-axonally where they induce a strong type 1 immune response that involves Th1, CD8 and B cell entry across the blood brain barrier and virus clearance in the absence of overt sequelae. Intranasal infection with attenuated RABV prolonged the survival of mice bearing established GL261 brain tumors. Despite the failure of virus spread to the tumor, infection resulted in significantly enhanced tumor necrosis, extensive CD4 T cell accumulation and high levels of the proinflammatory factors IFNy, TNFa, and iNOS in the TME merely 4 days after infection, before significant virus spread or the appearance of RABV-specific immune mechanisms in CNS tissues. While the majority of g CD4 cells appeared functionally inactive, the proinflammatory changes in the TME later resulted in the loss of accumulating M2 and increased M1 TAM. Mice deficient in the Th1 transcription factor Tbet did not gain any survival advantage from RABV infection, exhibiting only limited tumor necrosis and no change in TME cytokines or TAM phenotype, highlighting the importance of type 1 mechanisms in this process.

Safe and effective two-in-one replicon-and-VLP minispike vaccine for COVID-19: Protection of mice after a single immunization

“…dose of vaccine, and boost vaccination with the identical virus in the same hind leg further boosted VNA activity to levels superior to those of COVID-19 patients. VSV and RABV infections are known to induce a strong Th1 biased antiviral and anticancer immune response [93,94]. This holds also true for VSVΔG-minispike-eGFP vaccination, as indicated by preliminary results from rats.…”

TNFα secreted by glioma associated macrophages promotes endothelial activation and resistance against anti-angiogenic therapy

“…Although IL-8 and its major cognate receptor, CXCR1, are not present in mouse cells, MIP-2 and KC are suggested to be functional homologues [ 17 , 23 , 24 , 43 ]. Both MIP-2 and CCL2 are expressed by GL261 tumor cells [ 5 , 9 , 42 ]. Consistent with human GBM cell lines, CM from GL261 stimulated macrophages (Mφ-GL261) which in turn upregulated expression of VCAM1 and ICAM1 but not VEGF compared to macrophages conditioned with normal mouse astrocytes (Mφ-NMA) (Fig.…”

Safe and effective two-in-one replicon-and-VLP minispike vaccine for COVID-19

“…dose of vaccine, and boost vaccination with the identical virus in the same hind leg further boosted VNA activity to levels superior to those of COVID-19 patients. VSV infection is known to induce a strong Th1 biased antiviral and anticancer immune response (Bongiorno et al, 2017; De Giovanni et al, 2020). This holds also true for VSVΔG-minispike-eGFP vaccination, as indicated by preliminary results from rats.…”