Abstract 5835: Targeting discoidin domain receptor 1 (DDR1) reverses glioma immune suppression by remodeling collagen fiber architecture
Authors: Faisal Syed M. , Comba Andrea , Varela Maria L. , Argento Anna E. , Brumley Emily , West Molly E. , Haase Santiago , Mujeeb Anzar A. , Abel Clifford , Barissi Marcus N. , Clewner Jarred E. , Stack Brooklyn , Abbud Grace A. , Castro Maria G. , Lowenstein Pedro R. 
Published: April 2023

Glioblastoma (GBM) is the most aggressive and immunosuppressive form of brain tumor, and its treatment remains a large, unmet medical need. Recently, we introduced oncostreams to refer to dynamic multicellular neuropathological structures that facilitate glioma cell growth and invasion into the normal brain. Moreover, we have shown that targeting Col1α1 within gliomas eradicates oncostreams and prolongs median survival in two genetic murine models. However, the signaling that collagen utilizes to maintain the glioma tumor microenvironment is still unknown. Our RNA-seq data show that collagen receptor DDR1 is overexpressed in genetically engineered glioma mouse models (GEMMs) including NPA (NRAS/shp53/shATRX), NPD (NRAS/shp53/PDGFβ), and NPAI (NRAS/shp53/shATRX/IDH1R132H) compared to healthy mouse brain tissue. We discovered that pharmacological inhibition of DDR1 radio-sensitized gliomas in vitro and dismantled oncostreams ex vivo, imaged with time-lapse confocal microscopy. GEMMs of DDR1 knockdown (NRAS/shp53/shATRX/shDDR1) using the Sleeping Beauty transposase system significantly increased median survival. This suggests that gliomas employ DDR1 mediated mechanisms to promote the immunosuppressive TME and thus stimulate tumor growth. Inhibition of DDR1 within gliomas enhanced intratumoral infiltration of CD45+, and CD3+ immune cells at the tumor core and invasive tumor border and prolonged median survival in GEMMs of glioma. We postulate that glioma DDR1 blocks immune-surveillance by enhancing collagen fiber alignment, which we assessed using collagen-specific second-harmonic generation microscopy. In human datasets such as CGGA and TCGA, DDR1 expression negatively correlates with PTPRC (CD45) gene expression. Furthermore, our results show that DDR1 inhibition suppresses oncostream formation, impairs glioma cell proliferation (PCNA+) and remodeled the tumor microenvironment by lowering Iba1+ glioma-associated microglia. We propose that DDR1 inhibition within glioma cells reprograms the TME to an immune-stimulatory state with enhanced radio-sensitivity. Targeting the DDR1 collagen receptor is a novel and highly promising avenue for GBM therapeutics.

Citation Format: Syed M. Faisal, Andrea Comba, Maria L. Varela, Anna E. Argento, Emily Brumley, Molly E. West, Santiago Haase, Anzar A. Mujeeb, Clifford Abel, Marcus N. Barissi, Jarred E. Clewner, Brooklyn Stack, Grace A. Abbud, Maria G. Castro, Pedro R. Lowenstein. Targeting discoidin domain receptor 1 (DDR1) reverses glioma immune suppression by remodeling collagen fiber architecture [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5835.