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

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

doi:10.1172/jci.insight.157612

Cited by 11 publications

(8 citation statements)

References 76 publications

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“…One study found that high levels of traditionally “M1 markers” such as IL-6 and IL-1β were expressed by the same macrophages expressing traditionally “M2 markers” like matrix metalloproteinase (MMP)-1 and fibronectin 1 (FN1) ( 6 ). It has been shown that CD45+ myeloid cells in the GBM TME express markers of immune activation as well as immune suppression ( 42 ). A preclinical study detailed that treatment with anti-PD-1 therapy induced macrophage and microglia polarization towards a proinflammatory phenotype in glioma of CD8 -/- mice, suggesting that the therapeutic effect of PD-1 blockade may be due to innate rather than adaptive immune system function ( 28 ).…”

Section: Discussionmentioning

confidence: 99%

Myeloid Cell Classification and Therapeutic Opportunities Within the Glioblastoma Tumor Microenvironment in the Single Cell-Omics Era

et al. 2022

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The glioma tumor microenvironment (TME) is complex and heterogeneous, and multiple emerging and current technologies are being utilized for an improved comprehension and understanding of these tumors. Single cell analysis techniques such as single cell genomic and transcriptomic sequencing analysis are on the rise and play an important role in elucidating the glioma TME. These large datasets will prove useful for patient tumor characterization, including immune configuration that will ultimately influence therapeutic choices and especially immune therapies. In this review we discuss the advantages and drawbacks of these techniques while debating their role in the domain of glioma-infiltrating myeloid cells characterization and function.

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Section: Discussionmentioning

confidence: 99%

Myeloid Cell Classification and Therapeutic Opportunities Within the Glioblastoma Tumor Microenvironment in the Single Cell-Omics Era

et al. 2022

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“…The notion of using derivatives of nearest neighbour methods and cell proportion quantification for identifying clusters has been tackled also in previous literature [24, 25]. In our study, each tumor was sampled in triplicate from the centre of the tumour and the single cell data is not extracted from luminal side and advancing edge [26].…”

Section: Resultsmentioning

confidence: 99%

“…The notion of using derivatives of nearest neighbour methods and cell proportion quantification for identifying clusters has been tackled also in previous literature [24,25].…”

Section: Two Distinct Clusters Within Stage III Colorectal Cancer Tum...mentioning

confidence: 99%

Spatial Effects of Infiltrating T cells on Neighbouring Cancer Cells and Prognosis in Stage III CRC patients

Azimi,

Cho,

Bozkurt

et al. 2024

Preprint

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Colorectal cancer (CRC) is one of the most frequently occurring cancers, but prognostic biomarkers identifying patients at risk of recurrence are still lacking. In this study, we aimed to investigate in more detail the spatial relationship between intratumoural T cells, cancer cells, and cancer cell hallmarks, as prognostic biomarkers in stage III colorectal cancer patients. We conducted multiplexed imaging of 56 protein markers at single cell resolution on resected fixed tissue from stage III CRC patients who received adjuvant 5fluorouracilbased chemotherapy. Images underwent segmentation for tumour, stroma and immune cells, and cancer cell state protein marker expression was quantified at a cellular level. We developed a Python package for estimation of spatial proximity, nearest neighbour analysis focusing on cancer cell T cell interactions at single cell level. In our discovery cohort (MSK), we processed 462 core samples (total number of cells: 1,669,228) from 221 adjuvant 5FU-treated stage III patients. The validation cohort (HV) consisted of 272 samples (total number of cells: 853,398) from 98 stage III CRC patients. While there were trends for an association between percentage of cytotoxic T cells (across the whole cancer core), it did not reach significance (Discovery cohort: p = 0.07, Validation cohort: p = 0.19). We next benchmarked our region-based nearest neighbourhood approach to determine the spatial relationships between cytotoxic T cells, helper T cells and cancer cell clusters. In the both cohorts, we found that lower distance between cytotoxic T cells, T helper cells and cancer cells was significantly associated with increased disease-free survival. An unsupervised trained model that clustered tumours based on the median distance between immune cells and cancer cells, as well as protein expression profiles, successfully classified patients into lowrisk and highrisk groups (Discovery cohort: p = 0.01, Validation cohort: p = 0.003).

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“…In addition, there was no evidence of intracranial beneficial responses with lack of extracranial progression (72,73). In addition to a meaningful peripheral immune response during checkpoint blockade therapy, increased T cell numbers and cytolytic interactions with tumor cells might arbitrate successful intracranial responses following immunotherapy (43,76). PD-1 expression was also found in myeloid-derived suppressor cells, CD11b + F4/80 + macrophages, and CD11c + MHCII + dendritic cells in the tumor and the spleen of melanoma-bearing mice, albeit at different levels.…”

Section: R E V I E W S E R I S : I M M U N E E N V I R O N M E N T I ...mentioning

confidence: 99%

Immune checkpoint blockade in glioblastoma: from tumor heterogeneity to personalized treatment

Arrieta¹,

Dmello²,

McGrail³

et al. 2023

Journal of Clinical Investigation

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Conflict of interest: VAA and AMS are authors of a patent filed by Northwestern University related to predicting the response to immunotherapy in gliomas (US2021071138). AMS has received in-kind and/or funding support for research from Agenus, Bristol Myers Squibb, and Carthera. RS has acted or is acting as a scientific advisor or has served on advisory boards for Alpheus Medical (formerly Craniovation), AstraZeneca, Boston Scientific, Carthera, Celularity, GT Medical, Insightech, Lockwood (BlackDiamond), Northwest Biotherapeutics, Novocure, Syneos Health (Boston Biomedical), TriAct Therapeutics, and Varian Medical Systems. ABH serves on the advisory board of Caris Life Sciences and the WCG Oncology Advisory Board; receives royalty and milestone payments from DNAtrix for the licensing of "Biomarkers and combination therapies using oncolytic virus and immunomodulation" (patent 11,065,285); and is supported by research grants from Celu larity, Codiak BioSciences, and AbbVie. She additionally has active granted patents for "miRNA for treating cancer and for use with adoptive immunotherapies" (patent 9,675,633) and "Concurrent chemotherapy and immuno therapy" (patent 9,399,662), with a patent pending for "Low intensity ultrasound combination cancer therapies" (international applications PCT/US2022/019435 and US 63/158,642).

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

Cited by 11 publications

References 76 publications

Myeloid Cell Classification and Therapeutic Opportunities Within the Glioblastoma Tumor Microenvironment in the Single Cell-Omics Era

Myeloid Cell Classification and Therapeutic Opportunities Within the Glioblastoma Tumor Microenvironment in the Single Cell-Omics Era

Spatial Effects of Infiltrating T cells on Neighbouring Cancer Cells and Prognosis in Stage III CRC patients

Immune checkpoint blockade in glioblastoma: from tumor heterogeneity to personalized treatment

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