Is Host Metabolism the Missing Link to Improving Cancer Outcomes?

For the past 100 years, oncologists have relentlessly pursued the destruction of tumor cells by surgical, chemotherapeutic or radiation oncological means. Consistent with this focus, treatment plans are typically based on key characteristics of the tumor itself such as disease site, histology and staging based on local, regional and systemic dissemination. Precision medicine is similarly built on the premise that detailed knowledge of molecular alterations of tumor cells themselves enables better and more effective tumor cell destruction. Recently, host factors within the tumor microenvironment including the vasculature and immune systems have been recognized as modifiers of disease progression and are being targeted for therapeutic gain. In this review, we argue that-to optimize the impact of old and new treatment options-we need to take account of an epidemic that occurs independently of-but has major impact on-the development and treatment of malignant diseases. This is the rapidly increasing number of patients with excess weight and its\u27 attendant metabolic consequences, commonly described as metabolic syndrome. It is well established that patients with altered metabolism manifesting as obesity, metabolic syndrome and chronic inflammation have an increased incidence of cancer. Here, we focus on evidence that these patients also respond differently to cancer therapy including radiation and provide a perspective how exercise, diet or pharmacological agents may be harnessed to improve therapeutic responses in this patient population

Expression of Interferon Gamma by a Recombinant Rabies Virus Strongly Attenuates the Pathogenicity of the Virus via Induction of Type I Interferon.

UNLABELLED: Previous animal model experiments have shown a correlation between interferon gamma (IFN-γ) expression and both survival from infection with attenuated rabies virus (RABV) and reduction of neurological sequelae. Therefore, we hypothesized that rapid production of murine IFN-γ by the rabies virus itself would induce a more robust antiviral response than would occur naturally in mice. To test this hypothesis, we used reverse engineering to clone the mouse IFN-γ gene into a pathogenic rabies virus backbone, SPBN, to produce the recombinant rabies virus designated SPBNγ. Morbidity and mortality were monitored in mice infected intranasally with SPBNγ or SPBN(-) control virus to determine the degree of attenuation caused by the expression of IFN-γ. Incorporation of IFN-γ into the rabies virus genome highly attenuated the virus. SPBNγ has a 50% lethal dose (LD50) more than 100-fold greater than SPBN(-). In vitro and in vivo mouse experiments show that SPBNγ infection enhances the production of type I interferons. Furthermore, knockout mice lacking the ability to signal through the type I interferon receptor (IFNAR(-/-)) cannot control the SPBNγ infection and rapidly die. These data suggest that IFN-γ production has antiviral effects in rabies, largely due to the induction of type I interferons. IMPORTANCE: Survival from rabies is dependent upon the early control of virus replication and spread. Once the virus reaches the central nervous system (CNS), this becomes highly problematic. Studies of CNS immunity to RABV have shown that control of replication begins at the onset of T cell entry and IFN-γ production in the CNS prior to the appearance of virus-neutralizing antibodies. Moreover, antibody-deficient mice are able to control but not clear attenuated RABV from the CNS. We find here that IFN-γ triggers the early production of type I interferons with the expected antiviral effects. We also show that engineering a lethal rabies virus to express IFN-γ directly in the infected tissue reduces rabies virus replication and spread, limiting its pathogenicity in normal and immunocompromised mice. Therefore, vector delivery of IFN-γ to the brain may have the potential to treat individuals who would otherwise succumb to infection with rabies virus

Therapeutic modulation of the tumor-promoting immune type 2 microenvironment in malignant glioma by the induction of a type 1 response to attenuated rabies virus

Malignant glioma is an aggressive and invasive tumor associated with a high frequency of M2 polarized tumor associated macrophages and an immunosuppressive tumor microenvironment that promotes tumor growth and function. The unacceptably low survival rates of patients with high grade astrocytoma and glioblastoma have not been improved in decades by standard care. Immune- based therapy seeks to provide better outcomes through various strategies that promote glioma-specific immunity, but many of these strategies have yet to improve long term patient survival. Although the tumor is present within the central nervous system, which is somewhat isolated from the peripheral immune system by the blood-brain barrier, immunity naturally develops in response to glioma antigens. This presumably occurs in part through the release of glioma-derived exosomes, small vesicles containing concentrated tumor-derived cargo, which are found in peripheral fluids. Tumor exosomes generate type 2 biased responses and promote M2 monocyte activation, consequently contributing to tumor supportive macrophage populations. In contrast, the response accompanying neurotropic, attenuated rabies virus clearance from the CNS is associated with the production of type 1 proinflammatory factors in brain tissue, enhanced blood-brain barrier permeability, and effector entry into the CNS. Data presented here indicate that RABV infection can promote both mouse and human glioma exosome- specific Th1 responses, yet glioma exosomes from both species have inherent Th2-biasing properties, likely due to immunoregulatory miRNA content, and can shift the rabies virus response away from Th1. Furthermore, neuroinvasive rabies virus infection of mice with established brain tumors does not impact tumor-specific humoral responses, but prolongs survival and enhances tumor necrosis, primarily by triggering a proinflammatory shift in the tumor microenvironment resulting in re-polarization of tumor associated macrophages. Mechanistically these effects depend on the Th1 immune response to rabies virus as Tbet-/- mice derive no therapeutic benefit from infection. The data show that glioma derived factors fundamentally bias immune responses to Th2, but also highlight the importance of type 1 immune responses in overcoming pro-tumor factors and M2 macrophages in the tumor microenvironment. These findings have implications for the development of effective malignant glioma immunotherapies