Central nervous system immune interactome is a function of cancer lineage, tumor microenvironment, and STAT3 expression

Hinda Najem, Martina Ott, Cynthia Kassab, Arvind Rao, Ganesh Rao, Anantha Marisetty, Adam M. Sonabend, Craig Horbinski, Roel Verhaak, Anand Shankar, Santhoshi N. Krishnan, Frederick S. Varn, Víctor A. Arrieta, Pravesh Gupta, Sherise D. Ferguson, Jason T. Huse, Gregory N. Fuller, James P. Long, Daniel E. Winkowski, Ben A. FreibergCharles David James, Leonidas C. Platanias, Maciej S. Lesniak, Jared K. Burks, Amy B. Heimberger*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

BACKGROUND. Immune cell profiling of primary and metastatic CNS tumors has been focused on the tumor, not the tumor microenvironment (TME), or has been analyzed via biopsies. METHODS. En bloc resections of gliomas (n = 10) and lung metastases (n = 10) were analyzed via tissue segmentation and high-dimension Opal 7-color multiplex imaging. Single-cell RNA analyses were used to infer immune cell functionality. RESULTS. Within gliomas, T cells were localized in the infiltrating edge and perivascular space of tumors, while residing mostly in the stroma of metastatic tumors. CD163+ macrophages were evident throughout the TME of metastatic tumors, whereas in gliomas, CD68+, CD11c+CD68+, and CD11c+CD68+CD163+ cell subtypes were commonly observed. In lung metastases, T cells interacted with CD163+ macrophages as dyads and clusters at the brain-tumor interface and within the tumor itself and as clusters within the necrotic core. In contrast, gliomas typically lacked dyad and cluster interactions, except for T cell CD68+ cell dyads within the tumor. Analysis of transcriptomic data in glioblastomas revealed that innate immune cells expressed both proinflammatory and immunosuppressive gene signatures. CONCLUSION. Our results show that immunosuppressive macrophages are abundant within the TME and that the immune cell interactome between cancer lineages is distinct. Further, these data provide information for evaluating the role of different immune cell populations in brain tumor growth and therapeutic responses.

Original languageEnglish (US)
Article numbere157612
JournalJCI Insight
Volume7
Issue number9
DOIs
StatePublished - May 9 2022

Funding

This research was supported by NIH grant NS120547, a Developmental Research Project award through P50CA221747, ReMission Alliance, institutional funding from Northwestern University and the Lurie Comprehensive Cancer Center, and gifts from the Mosky family and Perry McKay. This research was performed at the Flow Cytometry & Cellular Imaging Core Facility at The University of Texas MD Anderson Cancer Center, which is supported, in part, by NIH grant CA016672 and the National Cancer Institute Research Specialist award 1 R50 CA243707. AR and SNK were supported by the Cancer Center Support Grant Bioinformatics Shared Resource (5 P30 CA046592), a gift from Agilent Technologies, a Research Scholar Grant from the American Cancer Society (RSG-16-005-01), and a Precision health Investigator Award from University of Michigan Precision Health to AR, along with L. Rozek and M. Sartor. AR and SNK were also partially supported by the National Cancer Institute (R37-CA214955) and by University of Michigan startup institutional research funds. AS was supported by a Biomedical Informatics and Data Science Training Grant (T32GM141746). FUNDING. This study was supported by the NIH (NS120547), a Developmental research project award (P50CA221747), ReMission Alliance, institutional funding from Northwestern University and the Lurie Comprehensive Cancer Center, and gifts from the Mosky family and Perry McKay. Performed in the Flow Cytometry & Cellular Imaging Core Facility at MD Anderson Cancer Center, this study received support in part from the NIH (CA016672) and the National Cancer Institute (NCI) Research Specialist award 1 (R50 CA243707). Additional support was provided by CCSG Bioinformatics Shared Resource 5 (P30 CA046592), a gift from Agilent Technologies, a Research Scholar Grant from the American Cancer Society (RSG-16-005-01), a Precision Health Investigator Award from University of Michigan (U-M) Precision Health, the NCI (R37-CA214955), startup institutional research funds from U-M, and a Biomedical Informatics & Data Science Training Grant (T32GM141746).

ASJC Scopus subject areas

  • General Medicine

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