Tmic-19. knockdown of tumor-derived osteopontin/spp1 or application of a blocking peptide restores anti-tumor responses in experimental rat gliomas

Malignant glioma produced factors that attract and re-program microglia and infiltrating peripheral macrophages into proinvasive, immunosuppressive cells. This creates immunosuppressive milieu and inhibits responses of infiltrating T cells. Recently, we identified glioma-processed osteopontin/Spp1 as a major microglia-activating factor. Spp1 is a small glycoprotein, interacting via a RGD motif with integrin receptors on immune cells and via a CD44 binding domain with a CD44 on tumor cells. Tumor-processed Spp1 induces the pro-invasive re-programming of microglia in vitro. Knockdown of Spp1 in C6 glioma inhibits growth of intracranial gliomas and reduces the number of microglia/macrophages expressing Arg1 and CD163, markers of a protumorigenic phenotype. Moreover, T lymphocytes infiltrating Spp1-depleted gliomas show signs of restoration of antitumor activity and exhibit upregulated expression of cytotoxic mediators. To investigate if protumorigenic effects of Spp1 depends on its support for glioma cells self-renewal or interactions with microenvironment, we re-expressed constructs coding for the wild type Spp1, CD44 binding domain lacking or the RGD mutated Spp1, in glioma cells lacking endogenous Spp1 and performed whole brain imaging to measure resulting tumors. Re-expression of the RGD mutated Spp1 did not restore tumor growth in vivo suggesting that interactions with integrin receptors on microglia is vital for tumor growth. We designed and tested a 7-aa peptide interferi...
Source: Neuro-Oncology - Category: Cancer & Oncology Authors: Tags: TUMOR MICROENVIRONMENT Source Type: research