Abstract 2169: Tumor-myeloid cell interactions are dynamic and influence the evolutionary trajectory of adult diffuse glioma
Authors: Varn Frederick S. , Johnson Kevin C. , Barthel Floris P. , Kim Hoon , Wade Taylor , Lodha Disha , Ajaib Shoaib , Ahmed Nazia , Garofano Luciano , D'Angelo Fulvio , Stead Lucy , Noushmehr Houtan , Iavarone Antonio , Verhaak Roel ,   The GLASS Consortium
Published: July 2021

Abstract
Diffuse glioma is an aggressive brain cancer that is characterized by a poor prognosis and a universal resistance to therapy. The evolutionary processes behind this resistance remain unclear. Previous studies by the Glioma Longitudinal Analysis (GLASS) Consortium have indicated that therapy-induced selective pressures shape the genetic evolution of glioma in a stochastic manner. However, single cell studies have revealed that malignant glioma cells are highly plastic and transition their cell state in response to diverse challenges, including changes in the immune response and the administration of standard-of-care therapy. Interactions between these factors remain poorly understood, making it difficult to predict how a patient's tumor will evolve from diagnosis to recurrence. To investigate these factors, we collected RNAseq data from 151 pre- and post-treatment tumor pairs, 101 of which also had matched whole exome or whole genome sequencing. Together, this dataset represents the largest collection of longitudinal multiomic glioma data yet assembled. We integrated this dataset with representative glioma single cell RNAseq data to implement digital cytometry approaches that quantified the microenvironmental composition of each tumor and reconstructed their tumor and immune cell state-specific gene expression profiles. In both IDHwt and IDHmut glioma, the tumor microenvironment was dominated by myeloid cells. The myeloid compartment of IDHwt tumors more closely resembled blood-derived macrophages, while myeloid cells in IDHmut tumors were more similar to microglia. While therapy did not alter the balance between macrophages and microglia in IDHwt tumors, myeloid cells in IDHmut tumors that increased grade following therapy had fewer microglia characteristics. Myeloid cells in mesenchymal glioma exhibited a distinct gene expression signature compared to those in non-mesenchymal tumors, and this signature was upregulated in the myeloid cells of tumors that acquired this phenotype following therapy. Receptor-ligand analyses revealed that this mesenchymal phenotype was associated with interactions between differentiated-like tumor cells and myeloid cells, suggesting a potential mechanism of mesenchymal transformation. Radiation therapy did not alter the composition or transcriptional activity of the glioma microenvironment but did associate with increased synaptic plasticity in stem cell-like and differentiated-like tumor cells. Collectively, our results suggest that tumor-myeloid cell interactions in glioma are dynamic and capable of shaping tumor evolution following the administration of therapy. Clinically targeting these interactions may allow for better control of malignant cell state shifts over time, creating new opportunities for disease management.
Citation Format: Frederick S. Varn, Kevin C. Johnson, Floris P. Barthel, Hoon Kim, Taylor Wade, Disha Lodha, Shoaib Ajaib, Nazia Ahmed, Luciano Garofano, Fulvio D'Angelo, Lucy Stead, Houtan Noushmehr, Antonio Iavarone, Roel Verhaak, The GLASS Consortium. Tumor-myeloid cell interactions are dynamic and influence the evolutionary trajectory of adult diffuse glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2169.