STTT Chinese Academy of Medical Sciences Zhu Hongxia/Xu Ningzhi Reveals New Potential Treatment Targets for Colorectal Cancer

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iNature macrophages are one of the most abundant immune cells in colorectal cancer (CRC)
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Re-domestication of tumor-associated macrophages (TAM) to transform from pro-tumor activity to anti-tumor activity is an attractive treatment strategy that deserves further study
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However, little is known about the key pathways activated in TAM
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On October 20, 2021, Zhu Hongxia and Xu Ningzhi, the State Key Laboratory of Molecular Oncology, Chinese Academy of Medical Sciences/Peking Union Medical College Cancer Hospital, jointly published an online communication titled "XBP1 regulates the protumoral function" in Signal Transduction and Targeted Therapy (IF=18.
19) "of tumor-associated macrophages in human colorectal cancer" research paper, this study sorts the CD206+ TAM infiltrated in CRC, and then conducts RNA-seq analysis
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The study found that differentially expressed genes were enriched in the unfolded protein response/endoplasmic reticulum stress response process, and XBP1 splicing/activation was particularly observed in TAM
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 The activation of XBP1 in TAM promotes the growth and metastasis of CRC
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The ablation of XBP1 inhibited the expression of TAM's pro-tumor cytokine characteristics, including IL-6, VEGFA and IL-4
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At the same time, XBP1 depletion can directly inhibit the expression of SIRPα and THBS1, thereby blocking the "don't eat me" recognition signal and enhancing phagocytosis
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Therapeutic XBP1 gene editing using AAV2-sgXBP1 enhances anti-tumor activity
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In summary, XBP1 activation in TAM drives the progression of CRC by increasing the expression and secretion of tumor-promoting cytokines and inhibiting macrophage phagocytosis
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Targeting the XBP1 signal in TAM may be a potential strategy for CRC treatment
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The infiltration of immune cells in colorectal cancer (CRC) contributes to tumor occurrence, progression and treatment response
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Tumor-related immunotherapy is considered to be a new frontier in cancer treatment
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Although many methods have been tested in clinical trials for patients with colorectal cancer, including PD-1/PD-L1 targeting and CTLA-4 targeting, none of these methods have achieved satisfactory results
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Macrophages are one of the most abundant immune cells observed in CRC, and those cells that infiltrate the tumor microenvironment are usually defined as tumor-associated macrophages (TAM)
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Single-cell RNA-seq analysis identified two different TAM subsets in the CRC tumor microenvironment
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These two subsets show different functions.
One subset expresses genes involved in phagocytosis and antigen presentation, while the other subset shows more angiogenic characteristics
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Therefore, exhausting all TAM may be problematic
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In the tumor microenvironment, macrophages may change from an anti-tumor phenotype to a tumor-promoting phenotype based on environmental stimuli
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Therefore, re-domesticating TAM to transform from pro-tumor activity to anti-tumor activity is an attractive strategy
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The article pattern (picture from Signal Transduction and Targeted Therapy) activated unfolded protein response (UPR) is involved in most signs of cancer
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The IRE1α-XBP1 pathway is the most conservative process associated with UPR
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When activated, IRE1α cleaves XBP1 mRNA, thereby inducing the expression of activated XBP1, leading to effective transcriptional activity
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 Recent studies have shown that the IRE1α-XBP1 pathway is involved in the immune differentiation, activation and cytokine expression of immune cells
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XBP1 has been reported in dendritic cells and T cells in the microenvironment of ovarian cancer.
Targeting XBP1 in dendritic cells or T cells restores the anti-tumor immunity of these cells, thereby prolonging the survival time of the host
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Endoplasmic reticulum (ER) stress also plays an important role in TAM by regulating the production of IL-6 and TNF-α
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IL-4 induced polarization of macrophages induces ER stress, and inhibition of ER stress may prevent polarization
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In cancer, the tumor-promoting function of TAM promotes the expression of cell surface receptors, cytokines, chemokines and enzymes
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Inhibition of IRE1α-XBP1 in macrophages may attenuate the surface expression of CD86 and PD-L1
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Therefore, the XBP1 pathway targeting TAM may be a new strategy for CRC immunotherapy
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This study evaluated the role of XBP1 in TAM associated with colon cancer
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XBP1 splicing was observed in TAMs of colorectal cancer patients and mouse models
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XBP1 enhances the tumor-promoting function of TAM
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The loss of XBP1 changes the expression characteristics of cytokines and promotes the phagocytosis of tumor cells by macrophages by destroying self-recognition
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The results of this study indicate that XBP1 in TAM has the potential as a new therapeutic target for human colon cancer
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