Analysis of chemokine network in primary human glioblastoma

Abstract

Abstract Chemokines play an integral role in cancer immunoevasion by modulating leukocyte infiltration. They selectively increase the migration of immunosuppressive cells while impairing the infiltration of cytotoxic lymphocytes with potent antitumor activity. Some cancer-associated chemokines may also enhance tumor progression by acting as growth factors or promoting epithelial-mesenchymal transition. Here, we acquired fresh human glioblastoma (GBM) tissues to define chemokine expression patterns in GBM tumors by integrating bulk and single-cell RNA sequencing of both tumor and healthy brain tissues along with Luminex secretome profiling of GBM primary cell cultures. Extensive mapping of GBM-associated chemokines has enabled us to gain insight into intratumoral chemokine-mediated cell-to-cell communication. Among others, we identified CCL7 and midkine (MDK) to play a crucial role in the formation of the hostile tumor microenvironment (TME) in GBM. We hypothesize that these chemoattractants can facilitate the GBM tumor growth by recruiting M2 macrophages, promoting epithelial-mesenchymal transition, and activating the prosurvival PI3K-Akt pathway. Indeed, high expression of both chemokines was linked to poor overall survival. Additionally, by integrating the data, we further identified the cellular source of the most abundantly secreted chemokines in GBM tumors. Since immune cells require TME infiltration to mediate an appropriate antitumor response, impaired tumor infiltration is one of the critical limiting factors for cancer cell therapy. Our chemokine atlas provides novel targets to enhance adoptive cell therapies by improving the potential of effector cells for tumor homing and anticancer activities in GBM. This research was funded by the National Science Centre, Poland (2020/37/B/NZ6/02191), the Polish Ministry of Science and Higher Education (grant number DI2018 020548), and the National Centre for Research and Development (STRATEGMED3/307326/6/NCBR/2017).