Glioma-associated microglia/macrophages augment tumorigenicity in canine astrocytoma, a naturally occurring model of human glioma

Abstract

Background Glioma-associated microglia/macrophage (GAM) markedly influence glioma progression. Under the influence of transforming growth factor beta (TGFB), GAM are polarized toward a tumor-supportive phenotype. However, neither therapeutic targeting of GAM recruitment, nor TGF Beta (TGFB) signaling demonstrated efficacy in glioma patients despite efficacy in preclinical models, underscoring the need for a comprehensive understanding of the TGFB/GAM axis. Spontaneously occurring canine gliomas share many features with human glioma and provide a complementary translational animal model for further study. Given the importance of GAM and TGFB in human glioma, the aims of this study were to further define the GAM-associated molecular profile and the relevance of TGFB signaling in canine glioma that may serve as the basis for future translational studies. Methods GAM morphometry, levels of GAM-associated molecules, and the canonical TGFB signaling axis were compared in archived samples of canine astrocytomas versus normal canine brain. Further, the effect of TGFB on the malignant phenotype of canine astrocytoma cells was evaluated. Results GAMs diffusely infiltrated canine astrocytomas. GAM density was increased in high-grade tumors that correlated with a pro-tumorigenic molecular signature and up-regulation of the canonical TGFB signaling axis. Moreover, TGFB1 enhanced migration of canine astrocytoma cells in vitro. Conclusions Canine astrocytomas share a similar GAM-associated immune landscape with human adult glioma. Our data also support a contributing role for TGFB1 signaling in the malignant phenotype of canine astrocytoma. These data further support naturally occurring canine glioma as a valid model for investigation of GAM-associated therapeutic strategies for human malignant glioma.

Evaluation of immunologic parameters in canine glioma patients treated with an oncolytic herpes virus

“…Similar to human high-grade gliomas, increased microvascular proliferation in canine gliomas correlated with higher-grade [13] . The untreated canine glioma microenvironment for oligodendroglioma and astrocytoma was highly enriched for Iba1+ macrophages, and microglial cells but not CD3 + T or CD20 + B cells, both of which were found in very small numbers within the TME consistent with previous findings in canine glioma patients analyzed at necropsy [36][37][38][39] . Our findings are consistent with these studies and with what is seen in human glioblastoma multiforme, confirming the immunologically "cold" nature of these tumors [7,40] .…”

Microglia-Derived Olfactomedin-like 3 Promotes Pro-Tumorigenic Microglial Function and Malignant Features of Glioma Cells

“…The qPCR reactions consisted of primer pairs at a final concentration of 200 nM, 50 ng cDNA template, and 2× SSoAdvanced Universal SYBR Green Superix (Bio-Rad, Hercules, CA, USA) per manufacturer’s protocol on a CFXConnect (Bio-Rad, Hercules, CA, USA) machine as previously described [ 51 ]. All reactions were run as 20-µL triplicates, and the average Cq was used as the data point for a given sample.…”

Intratumoral Delivery of STING Agonist Results in Clinical Responses in Canine Glioblastoma

“…The presence of FoxP3 þ T cells in canine gliomas suggests a pro-tumorigenic state of their immune microenvironment. This is supported by recent functional studies of glioma-associated macrophages/microglia in canine tumors, showing upregulation of TGFb signaling and other pro-tumorigenic phenotypic markers (25). Only one of the subjects had analysis of the nature of the immune responses during the therapeutic window, whereas the others were during disease progression.…”