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Blockade of Myd88 signaling by a novel MyD88 inhibitor prevents colitis-associated colorectal cancer development by impairing myeloid-derived suppressor cells.

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单位： [1]Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Key Laboratory of Organ Transplantation, Ministry of Education, China NHC Key Laboratory of Organ Transplantation, China Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China. [2]Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China

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关键词： MyD88 signaling Myeloid-derived suppressor cells Colitis-associated colorectal cancer MyD88 inhibitor

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In cancer, myeloid-derived suppressor cells (MDSCs) are known to escape the host immune system by developing a highly suppressive environment. However, little is known about the molecular mechanism behind MDSC-mediated tumor cell evasion of the immune system. Toll-like receptor (TLR) signaling elicited in the tumor microenvironment has the potential to induce MDSC differentiations in different organs. Therefore, MDSC elimination by blocking the action of myeloid differentiation factor 88 (MyD88), which is a key adaptor-signaling molecule that affects TLR activity, seems to be an ideal tumor immunotherapy. Previous studies have proven that blocking MyD88 signaling with a novel MyD88 inhibitor (TJ-M2010-5, synthesized by Zhou's group) completely prevented colitis-associated colorectal cancer (CAC) development in mice.In the present study, we investigated the impact of the novel MyD88 inhibitor on the number, phenotype, and function of MDSC in the mice model of CAC.We showed that CAC growth inhibition was involved in diminished MDSC generation, expansion, and suppressive function and that MDSC-mediated immune escape was dependent on MyD88 signaling pathway activation. MyD88 inhibitor treatment decreased the accumulation of CD11b+Gr1+ MDSCs in mice with CAC, thereby reducing cytokine (GM-CSF, G-CSF, IL-1β, IL-6 and TGF-β) secretion associated with MDSC accumulation, and reducing the expression of molecules (iNOS, Arg-1 and IDO) associated with the suppressive capacity of MDSCs. In addition, MyD88 inhibitor treatment reduced the differentiation of MDSCs from myeloid cells and the suppressive capacity of MDSCs on the proliferation of activated CD4+ T cells in vitro.MDSCs are primary cellular targets of a novel MyD88 inhibitor during CAC development. Our findings prove that MyD88 signaling is involved in the regulation of the immunosuppressive functions of MDSCs. The novel MyD88 inhibitor TJ-M2010-5 is a new and effective agent that modulates MyD88 signaling to overcome MDSC suppressive functions, enabling the development of successful antitumor immunotherapy.© 2022. The Author(s).

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出版当年[2021]版：

大类 | 3 区医学

小类 | 3 区药学 4 区肿瘤学

最新[2025]版：

大类 | 3 区医学

小类 | 3 区药学 4 区肿瘤学

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出版当年[2020]版：

Q2 PHARMACOLOGY & PHARMACY Q3 ONCOLOGY

最新[2023]版：

Q2 ONCOLOGY Q2 PHARMACOLOGY & PHARMACY

影响因子： 3 最新[2023版] 2.9 最新五年平均 3.85 出版当年[2020版] 3.848 出版当年五年平均 3.525 出版前一年[2019版] 3.651 出版后一年[2021版]

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第一作者单位： [1]Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Key Laboratory of Organ Transplantation, Ministry of Education, China NHC Key Laboratory of Organ Transplantation, China Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China.

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Blockade of Myd88 signaling by a novel MyD88 inhibitor prevents colitis-associated colorectal cancer development by impairing myeloid-derived suppressor cells.

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