Abstract 69: Minimally invasive brain metastases are characterized by elevated immune cell infiltrate
Authors: Maritan Sarah M. , Karimi Elham , Dankner Matthew , Yu Miranda W. , Hernandez-Corchado Aldo , Rezanejad Morteza , Fallah Parvaneh , Fiset Benoit , Wei Yuhong , Lam Stephanie , Nehme Ali , Watson Ian R. , Park Morag , Riazalhosseini Yasser , Najafabadi Hamed , Petrecca Kevin , Guiot Marie-Christine , Quail Daniela F. , Walsh Logan A. , Siegel Peter M. 
Published: April 2023

Abstract
Background: Cancer metastasis to the brain is a common complication of advanced disease with limited therapeutic options. Inefficient treatment is influenced, in part, by the unique composition of the brain microenvironment. Brain metastases (BrM) grow in two distinct patterns, either as minimally invasive (MI) masses with well-defined borders, or as tumors with highly invasive (HI) growth into surrounding brain tissue. HI BrM are associated with poor prognoses compared to MI BrM; however, differences in the tumor immune microenvironments (TIME) between these two lesion types remain largely unknown. Here, we investigate how the TIME differs between HI and MI BrM.
Methods: We use Nanostring Digital Spatial Profiling coupled with the Cancer Transcriptome Atlas panel on 5 MI and 15 HI BrM patient samples (lung and breast cancer). This technique enables specific isolation of cancer cells at the tumor-brain interface and quantification of 1,825 cancer-specific RNA targets. Additionally, we perform imaging mass cytometry (IMC) on 119 BrM samples (lung cancer, breast cancer, melanoma, other) from 46 patients, encompassing over 350,000 cells. Samples represent BrM from various primary sites, and include patient-matched samples from the brain-tumor interface (‘margin’) or the centre of the metastatic lesion (‘core’).
Results: The Nanostring Digital Spatial Profiling revealed a list of 106 and 73 differentially expressed genes in MI vs HI breast and lung BrM, respectively. Gene set enrichment analyses revealed that an interferon gamma (IFNγ) pathway signature was enriched in MI BrM and lost in HI BrM, which was confirmed by immunohistochemical staining for pSTAT1, consistent with an “immune hot” TIME in MI BrM when compared to HI lesions. Using IMC technology, we identified 20 different cell types, activation states, and spatially-defined cellular neighbourhoods across our BrM patient samples. In comparison to MI samples, HI BrM have lower numbers of B cells, CD4+ T cells, and CD4- CD8- T cells in both the core and margin samples, and lower numbers of CD8+ T cells and regulatory T cells in the margin samples only.
Discussion: These data suggest that HI BrM invade into an immunosuppressed microenvironment while MI BrM are characterized by an active anti-tumor immune infiltrate. Together, this work suggests potential immune regulation of BrM invasion, which warrants further investigation.
Citation Format: Sarah M. Maritan, Elham Karimi, Matthew Dankner, Miranda W. Yu, Aldo Hernandez-Corchado, Morteza Rezanejad, Parvaneh Fallah, Benoit Fiset, Yuhong Wei, Stephanie Lam, Ali Nehme, Ian R. Watson, Morag Park, Yasser Riazalhosseini, Hamed Najafabadi, Kevin Petrecca, Marie-Christine Guiot, Daniela F. Quail, Logan A. Walsh, Peter M. Siegel. Minimally invasive brain metastases are characterized by elevated immune cell infiltrate [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 69.