Cytokine-armed vaccinia virus infects the mesothelioma tumor microenvironment to overcome immune tolerance and mediate tumor resolution

Abstract

Intratumoral (i.t.) administration of cytokine genes expressed by viral vectors represents a rational approach that induces cytokine secretion at the site they are needed, and i.t. vaccinia virus (VV) has shown promise in mesothelioma patients. However, we and others have shown that the mesothelioma tumor microenvironment includes macrophages, dendritic cells (DCs), and T cells. Therefore, we investigated which of these cell types are infected after exposure to VV or Fowlpox virus (FPV)-cytokine gene constructs. In vitro studies showed that mesothelioma tumor cells were resistant to FPV infection yet highly permissive to infection by VV vectors resulting in significant cytokine production and impaired proliferation. Macrophages secreted low levels of cytokine suggestive of resistance to overt infection. DCs transiently secreted virally derived cytokines, but did not mature during VV infection. VV inhibition of T cell proliferation was rescued by the interleukin (IL)-2 and IL-12 VV constructs. In vivo studies of murine mesotheliomas showed that i.t. injection of the parent VV could not hinder tumor progression. In contrast, the VV-cytokine constructs induced profound tumor regression. These data suggest that i.t. VV-cytokine gene constructs retard tumor growth by infecting mesothelioma cells and targeting the immune system through tumor-infiltrating DC and T cells.

Intratumoral interleukin-2/agonist CD40 antibody drives CD4+-independent resolution of treated-tumors and CD4+-dependent systemic and memory responses

“…In these studies, local i.t. treatment was used to modulate the mesothelioma tumor microenvironment; other reagents may elicit a similar response in this and other models [44,45]. Generating local inflammation via IL-2/anti-CD40 Ab therapy resulted in collaborating CD4 ?…”

Activation of CD1d-restricted natural killer T cells can inhibit cancer cell proliferation during chemotherapy by promoting the immune responses in murine mesothelioma

“…IL-12 has been shown to induce anti-tumor immunity against malignant mesothelioma [41,42]. Effect on tumor growth occurred when IL-12 was released within the tumor by co-administration of IL-12 gene transfected mesothelioma cells.…”

IL-2/CD40-activated macrophages rescue age and tumor-induced T cell dysfunction in elderly mice

“…Cells obtained from the peritoneal cavity of mice by washing with ice-cold PBS were incubated for 2-4 h at 37°C, after which non-adherent cells were removed; the remaining adherent population was >95 % F4/80 + macrophages (Jackaman and Nelson 2010). Where specified, macrophages were cultured overnight with 50 % AB1 mesothelioma-conditioned media, 50 % AE17 mesothelioma-conditioned media, 50 % LLconditioned media, M2 stimuli (20 ng/ml IL-4; Shenandoah Biotechnology, PA, USA), M1 stimuli (20 ng/ml IFN-γ, Shenandoah Biotechnology; and 1 μg/ml LPS, Sigma-Aldrich) or IL-2/anti-CD40 Ab (10 μg/ml of each, IL-2 obtained from Cetus Corporation, CA, USA; anti-CD40 Ab, or FGK45 obtained from AbSolutions, Western Australia).…”

“…Immunotherapy has shown promise in both cancers particularly mesothelioma (Bundell et al 2006;Jackaman et al 2003;Jackaman et al 2009;Jackaman et al 2012b;Jackaman et al 2008;Nelson 2010, Jackaman andNelson 2012;van Bruggen et al 2005); however, most preclinical analysis are performed in young adult mice and not representative of human cancers, such as mesothelioma, that usually occur in aging populations (Bianchi and Bianchi 2007). Furthermore, most immunotherapeutic strategies focus on T cell activation, yet T cell number and function decline with age meaning that other cells may have to be targeted (Haynes and Maue 2009).…”