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Transcriptome sequencing analysis of CSF-1Rhigh TAMs and CSF-1Rlow TAMs in colon adenocarcinoma.

ABSTRACT: Tumor-associated macrophages (TAMs) are a major component of the leukocyte and a heterogenous population in tumors. Recent reports have increasingly suggested that manipulating the function of TAMs may serve as a promising therapeutic strategy against advanced tumors. Our present work indicates that CSF-1R+ TAMs are abundantly found in a significant proportion of COAD specimens. Therefore，to determine the role of the CSF-1Rhigh TAMs in COAD, we sorted the CSF-1Rhigh TAMs and the CSF-1R low TAMs from the colon adenocarcinomas for Smart-seq2. We found that CSF-1Rhigh TAM infiltration involved in multiple tumor immune signaling pathways. CSF-1Rhigh TAMs mostly exhibited a immunosuppressive phenotypes, and were associated with enhanced levels of Treg cells. CSF-1R high TAMs promotes COAD progression by modulating tumor immunity environment

ORGANISM(S): Homo sapiens

PROVIDER: GSE193814 | GEO | 2022/03/31

REPOSITORIES: GEO

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Project description:Background: Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) is a hematopoietic growth factor and adjuvant in cancer immunotherapy via stimulation of dendritic cells/APCs. However, GM-CSF has yielded inconsistent results and its role regarding in vivo modulation of macrophages remains underexplored. We previously demonstrated that 100ng “high-dose” intratumor (IT) GM-CSF ablated tumor blood vessels and worsened tumor hypoxia after 3 weeks through tumor-associated macrophage (TAM) soluble VEGFR-1 production in PyMT murine breast cancer. Here, we investigate a role for “low-dose” IT GM-CSF on tumor oxygen and the impact on immunotherapy response, TAMs/myeloid cells, and TILs relative to “high-dose”. Methods: We performed IT injections of dose-specific GM-CSF or saline controls and then evaluated phenotypic effects after 3 weeks. We used Electron Paramagnetic Resonance Oximetry to measure and image in vivo tumor oxygen in real-time, and fluorescent immunohistochemistry to assess tumor blood vessels. IT GM-CSF doses were tested in priming PyMT tumors for sensitization to PD1. We performed RNA Sequencing of TAM and CD8 TIL to observe transcriptional changes coupled with flow cytometry of peripheral blood monocytes, tumor myeloid, and TIL populations in immunology cold" PyMT tumors response to dose-optimized GM-CSF. Lastly, we assessed and compared effects of IT GM-CSF on TAM and TIL in an immunologically “hot” 4T1 breast cancer model. Results: 5ng IT GM-CSF significantly increased PyMT tumor oxygen without augmenting tumor growth and promoted tumor vessel health via increased pericyte coverage. Priming of PyMT tumors with 5ng IT GM-CSF (“low-dose”, hypoxia reduced) sensitized “cold” PyMT tumors to PD1, but this synergy was not observed with 100ng (“high-dose”, hypoxia exacerbated). Immunologically, 5ng GM-CSF did not increase monocyte mobilization or alter phenotypic marker expression on TAMs, but reduced hypoxic and inflammatory transcriptional programs in macrophages and CD8 TIL isolated from PyMT tumors. 100ng increased infiltration of myeloid cells and TAMs but these TAMs had reduced MHCII expression, suggesting support of immune-suppressive TAM under hypoxia. Some tumors exhibited increased CD8 polyfunctionality either dose suggesting mild CD8 TIL priming. On the other hand, 100ng in “hot” 4T1 tumors resulted in increased TAM MHCII and other immunostimulatory molecules with moderate increases in CD8 TIL polyfunctionality and exhausted PD1hiTIM3+ phenotype, indicating that GM-CSF may have opposing effects on macrophage modulation based on tumor immunological status.

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Transcriptome sequencing analysis of CSF-1Rhigh TAMs and CSF-1Rlow TAMs in colon adenocarcinoma.

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