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Written by | Snow Moon
Mutations in tumor-associated genes produce antigens that can activate cytotoxic T lymphocytes CTLs
.
However, in tumors, CTL is usually in a state of suppression, with a dysfunctional state of failure
.
Although targeting PD-1 and PD-L1 can enhance CTL activity in tumor-draining lymph nodes and successfully improve tumor treatment effects, how to induce T cell depletion in tumors is poorly understood, and T cell depletion has not been reversed
in anti-PD-1/PD-L1 therapy.
Monocytes include monocytes, macrophages, and dendritic cells that can participate in innate immunity as well as initiate and modulate adaptive immune responses
as antigen-presenting cells.
Dendritic cell DCs can capture antigens in tumor tissue and migrate to lymph nodes to activate specific T cells
.
DC1 contains DC1, which is mainly determined by IRF8 differentiation, which can present exogenous antigens to CTL, and DC2 relies on IRF4 to regulate CD4+ T cells
.
In a variety of tumor models, the loss of DC1 impairs the initiation
of CTL.
On October 25, 2022, the team of Ming O.
Li from Memorial Sloan-Kettering Cancer Center and Cornell University delivered a speech on Immunity Tumor-associated macrophages expressing the transcription factor IRF8 article promoting T cell exhaustion in cancer
.
This article reveals that tumor-associated macrophages are regulated by IRF8, produce DC-like characteristics, and present tumor antigens to promote CD8+ T cell function depletion
.
The authors first detected changes in the mononuclear phagocyte system in the MMTV-PyMT (PyMT) breast cancer model, and found that the number of tumor-associated macrophages residing in tumor tissues increased, while the proportion of DC1 decreased, and DC2 did not change significantly
。 Most DC1 expresses CD103
, a marker associated with maturation and migration to secondary lymph nodes.
Transcriptome analysis of each cell population showed that tumor-associated macrophages shared common features with DCs, while monocytes and breast tissue macrophages had different characteristics
from tumor-associated macrophages, DC1 and DC2.
To investigate whether tumor-associated macrophages differentiated from ly6C+ monocytes are regulated by intrinsic transcription programs, the authors compared the differential expression of transcription factors in monocytes, breast tissue macrophages, and tumor-associated macrophages, and focused on the IRF family
that regulates the fate of multiple cells.
The authors found that IRF4 and IRF8 were expressed in opposite patterns in breast tissue macrophages and tumor-associated macrophages, and IRF8 was highly expressed
in tumor-associated macrophages.
In order to verify this expression pattern of IRF8, the authors tested it with a mouse model of IRF8-EGFP breast cancer and found that tumor-associated macrophages did indeed express higher levels of EGFP than monocytes and breast tissue macrophages, and DC1 also expressed higher levels of EGFP
.
Next, the authors used CD11cCreIrf8fl/fl PyMT mice (IRF8 in both DC and tumor-associated macrophages can be knocked out simultaneously) to analyze the effect of
IRF8 on tumor-associated macrophages and DC1.
The analysis showed that the number of tumor DC1 decreased significantly, and the expansion and maturation of tumor-associated macrophages were disrupted
.
Although the authors detected significant damage to CTL, tumor growth was not significantly different from
that of the control group.
The authors analyzed the transcriptome characteristics of tumor-associated macrophages isolated from CD11cCreIrf8fl/fl PyMT mice, and the results verified that IRF8 can drive the DC-like attribute characteristics in tumor-associated macrophages, and IRF8 activates gene expression programs of tumor-associated macrophages that are shared with DCs and facilitate antigen acquisition and presentation and interaction with
T cells.
IRF8 mediates the presentation of tumor antigens by tumor-associated macrophages and induces CTL expression of PD-1
.
To explore the in vivo effects of IRF8 in tumor-associated macrophages, the authors used MafBiCreIrf8fl/fl PyMT mice (IRF8 in mononuclei, tumor-associated macrophages, and breast tissue macrophages to be specifically knocked out).
。 The analysis found that tumor growth was inhibited
in the knockout group mice compared to the control group mice.
Comparing the changes in the proportion of individual cells in CD11cCreIrf8fl/fl PyMT mice, the authors concluded that DC1 is necessary for the activation of tumor-specific CD8+ T cells, and CD8+ T cells will be presented by tumor-associated macrophages expressing IRF8 in tumors, promoting T cell depletion and weakening anti-tumor immune responses
.
Finally, the authors verified that IRF8-dependent tumor-associated macrophages can also promote CD8+ T cell depletion
in a variety of human tumors.
This study revealed the important role of the transcription factor IRF8 in tumor-associated macrophages and explored its important contribution
to promoting CD8+ T cell depletion.
The role of IRF8-associated tumor macrophages in anti-PD-1 tumor therapy remains to be studied
.
Original link:
https://doi.
org/10.
1016/j.
immuni.
2022.
10.
002
Pattern maker: Eleven
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