​STM｜Hua Fang/Zhang Haizeng Collaborative Team Reports Targeted Inhibition of TRIB3 to Heat "Cold" Tumors - A New Strategy for Colon Cancer Immunotherapy

Editor-in-Chief | Colorectal cancer is the third most common tumor that seriously threatens human health in the world.
Surgery, chemotherapy, radiotherapy and targeted therapy are the main treatment methods
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However, once the patient develops drug resistance and metastasis, the treatment is in trouble
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The rise of immunotherapy has brought light to the treatment of colon cancer.
Unfortunately, only a small number of colon cancer patients with microsatellite instability or mismatch repair deficiency respond to immunotherapy, and these patients account for only 15% of the total number of colorectal cancer patients.

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The lack of CD8+ T cell infiltration is an important factor that prevents most colon cancer patients from benefiting from immunotherapy, and the cause of this "immune desert" remains unsolved
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On January 5, 2022, Professor Hua Fang's team from the State Key Laboratory of "Natural Drug Active Substances and Functions", Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College School of Medicine cooperated with the team of Professor Zhang Haizeng, Chinese Academy of Medical Sciences & Peking Union Medical College Cancer Hospital.
A research paper titled TRIB3 Reduces CD8+ T Cell Infiltration and Induces Immune Evasion by Repressing the STAT1-CXCL10 Axis in Colorectal Cancer was published as a cover article in Science Translational Medicine
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This study revealed that the pseudokinase protein Tribble 3 (TRIB3) is a key molecule in inducing immune escape from colon cancer, and clarified the molecular biological mechanism of abnormal homeostasis of TRIB3 under high glucose metabolic stress
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This work confirms that the targeted inhibition of TRIB3 is an important strategy to promote the "warming up of cold tumors", and provides a new idea for remodeling the immune microenvironment of colon cancer and improving the sensitivity of colorectal cancer immunotherapy
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Professor Hua Fang has long been concerned about the tumor-promoting effect of the pseudokinase protein TRIB3.
Past research work of the team has confirmed that there is abnormally high expression of TRIB3 in colon cancer.
TRIB3 enhances the stemness characteristics of tumor cells by up-regulating the Wnt/β-catenin signaling pathway, and promotes colonic Carcinogenesis and progression (Gastroenterology, 2019)
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In this study, the researchers found that the tumor suppressive effect caused by knockdown of TRIB3 in colon cancer cells was more pronounced in an immune-competent mouse model than in a nude mouse model, suggesting that the highly expressed TRIB3 in tumors may also act on tumor immune microbes.
environment
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Professor Hua Fang and Zhang Haizeng, director of the Colorectal Surgery Department of Cancer Hospital, launched a basic and clinical interdisciplinary collaborative research
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The team carried out in-depth research on tumor cell/immune cell co-culture system, subcutaneous transplanted tumor, colon cancer orthotopic transplanted tumor, colon cancer spontaneous model and colon cancer patient tissue samples.
Inhibits the infiltration of CD8+ T cells at tumor sites and reduces their killing activity
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Chemokines are a class of important proteins that mediate T cell recruitment, so does TRIB3 hinder the recruitment of CD8+ T cells to tumor sites by affecting the expression of certain chemokines? Using the CBA method, the researchers screened a series of chemokines and finally confirmed that TRIB3 hinders T cell migration by inhibiting the expression of CXCL10
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After elucidating the pro-immune escape mechanism of TRIB3, the researchers did not stop exploring
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They pondered that finding a way to reduce TRIB3 expression could improve colon cancer's response to immune checkpoint blockade therapy
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In previous work, the team has found that metabolic stress factors such as high glucose can induce elevated TRIB3 expression
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High glucose microenvironment is a metabolic factor that causes active protein acetylation modification
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From this phenomenon, the researchers confirmed that acetyltransferase P300 can mediate the acetylation of lysine 240 of TRIB3, which prevents the ubiquitination of lysine 197 of TRIB3 by the E3 ubiquitin ligase SIAH1 Modification and its degradation via the proteasomal pathway
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These results suggest that targeted inhibition of P300 acetyltransferase activity may be an effective approach to reduce TRIB3 expression
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Indeed, the specific inhibitor of P300, C646, can not only reduce the expression of TRIB3 protein and promote the recruitment of CD8+ T cells at the tumor site; the combination of C646 with PD-L1 or PD-1 antibody also significantly improves the resistance to immune checkpoint blockade therapy.
tumor effect
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The team's two studies on TRIB3 in colon cancer confirmed that targeting TRIB3 not only inhibited the stem cell-like properties of colon cancer cells, but also sensitized colon cancer to immunotherapy
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This suggests that specific inhibitors of TRIB3 may have the effect of "killing two birds with one stone" in the treatment of colon cancer, providing new ideas and targets for the treatment of colorectal cancer! Epidemiological data show that people with diabetes have a significantly higher risk of colorectal cancer than the general population and have a poor prognosis, but the mechanism is not fully elucidated
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In the present study, the researchers also confirmed that colon cancer patients with diabetes also had higher TRIB3 expression and less CD8+ T cell infiltration in tumor tissue compared with non-diabetic colon cancer patients
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Studies using a transgenic mouse model found that tissue-specific knockout of TRIB3 expression in intestinal epithelial cells significantly increased CD8+ T cell infiltration at tumor sites and inhibited the development and progression of spontaneous colon cancer in diabetic mice
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This finding also provides a new mechanism explanation for the clinical phenomenon of high incidence and poor prognosis of colon cancer in diabetic patients from the perspective of immune microenvironment for the first time
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Chinese Academy of Medical Sciences & Peking Union Medical College-Institute of Materia Medica Assistant Researcher Shang Shuang and postgraduate Yang Yuwei and Chen Fei are the co-first authors of this article.
Professor Hua Fang, Chinese Academy of Medical Sciences & Peking Union Medical College-Institute of Materia Medica and Chinese Academy of Medical Sciences & Zhang Haizeng, Director of Colorectal Surgery, Peking Union Medical College-Tumor Hospital, is the co-corresponding author of this article
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