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      PD‐L1/p‐STAT3 promotes the progression of NSCLC cells by regulating TAM polarization

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          Abstract

          PD‐L1 is closely related to the immune escape process of tumour cells, and targeted PD‐L1 clinical immunotherapy has been implemented. However, whether PD‐L1 is involved in TAM/M2 polarization in the TME of NSCLC and its specific mechanism remain unclear. In order to clarify the specific role of PD‐L1 in NSCLC and to seek new treatments for NSCLC, we designed a series of experimental studies. After constructing the co‐culture system and conditioned medium system, the proliferation, apoptosis, metastasis, angiogenesis, EMT process and stemness of NSCLC were detected by MTT, flow cytometry, Transwell, endothelial cell tube formation and western blot assays. The results showed that αPD‐L1 reversed TAM/M2 polarization by suppressing STAT3 phosphorylation in TAM/M2, therapy inhibiting NSCLC cell migration, angiogenesis, EMT process and stemness. However, αPD‐L1 had no effect on the proliferation and apoptosis abilities of NSCLC cells. In vivo experiments showed that αPD‐L1 inhibited lung metastasis of NSCLC and reversed TAM/M2 polarization in TME. The study investigates the mechanism by which PD‐L1 regulates TAMs polarization in TME and promotes malignant progression of NSCLC, providing a new theoretical basis for PD‐L1 targeted therapy of NSCLC.

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          Tumor Microenvironment

          Background and Objectives: The tumor microenvironment has been widely implicated in tumorigenesis because it harbors tumor cells that interact with surrounding cells through the circulatory and lymphatic systems to influence the development and progression of cancer. In addition, nonmalignant cells in the tumor microenvironment play critical roles in all the stages of carcinogenesis by stimulating and facilitating uncontrolled cell proliferation. Aim: This study aims to explore the concept of the tumor microenvironment by conducting a critical review of previous studies on the topic. Materials and Methods: This review relies on evidence presented in previous studies related to the topic. The articles included in this review were obtained from different medical and health databases. Results and Discussion: The tumor microenvironment has received significant attention in the cancer literature, with a particular focus on its role in tumor development and progression. Previous studies have identified various components of the tumor microenvironment that influence malignant behavior and progression. In addition to malignant cells, adipocytes, fibroblasts, tumor vasculature, lymphocytes, dendritic cells, and cancer-associated fibroblasts are present in the tumor microenvironment. Each of these cell types has unique immunological capabilities that determine whether the tumor will survive and affect neighboring cells. Conclusion: The tumor microenvironment harbors cancer stem cells and other molecules that contribute to tumor development and progression. Consequently, targeting and manipulating the cells and factors in the tumor microenvironment during cancer treatment can help control malignancies and achieve positive health outcomes.
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            Targeting Metabolism to Improve the Tumor Microenvironment for Cancer Immunotherapy.

            The growing field of immune metabolism has revealed promising indications for metabolic targets to modulate anti-cancer immunity. Combination therapies involving metabolic inhibitors with immune checkpoint blockade (ICB), chemotherapy, radiation, and/or diet now offer new approaches for cancer therapy. However, it remains uncertain how to best utilize these strategies in the context of the complex tumor microenvironment (TME). Oncogene-driven changes in tumor cell metabolism can impact the TME to limit immune responses and present barriers to cancer therapy. These changes also reveal opportunities to reshape the TME by targeting metabolic pathways to favor immunity. Here we explore current strategies that shift immune cell metabolism to pro-inflammatory states in the TME and highlight a need to better replicate physiologic conditions to select targets, clarify mechanisms, and optimize metabolic inhibitors. Unifying our understanding of these pathways and interactions within the heterogenous TME will be instrumental to advance this promising field and enhance immunotherapy.
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              Crosstalk between cancer cells and tumor associated macrophages is required for mesenchymal circulating tumor cell-mediated colorectal cancer metastasis

              Background Tumor-associated macrophages (TAMs) are major components of tumor microenvironment that frequently associated with tumor metastasis in human cancers. Circulating tumor cell (CTC), originating from primary tumor sites, is considered to be the precursors of tumor metastasis. However, the regulatory mechanism of TAMs in CTC-mediated tumor metastasis still remains unclear. Methods Immunohistochemical staining was used to detect the macrophages infiltration (CD68 and CD163), epithelial–mesenchymal transition (EMT) markers (E-cadherin and Vimentin) expression in serial sections of human colorectal cancer (CRC) specimens. Then, the correlations between macrophages infiltration and clinicopathologic features, mesenchymal CTC ratio, and patients’ prognosis were analyzed. A co-culture assay in vitro was used to evaluate the role of TAMs on CRC EMT, migration and invasion, and ELISA, luciferase reporter assay and CHIP were performed to uncover the underlying mechanism. Furthermore, an in vivo model was carried out to confirm the effect of TAMs on mesenchymal CTC-mediated metastasis. Results Clinically, CD163+ TAMs infiltrated in invasive front was associated with EMT, mesenchymal CTC ratio, and poor prognosis in patients with CRC. CRC–conditioned macrophages regulated EMT program to enhance CRC cells migration and invasion by secreting IL6. TAMs-derived IL6 activated the JAK2/STAT3 pathway, and activated STAT3 transcriptionally inhibited the tumor suppressor miR-506-3p in CRC cells. miR-506-3p, a key miRNA regulating FoxQ1, was downregulated in CRC cells, resulting in increased FoxQ1 expression, which in turn led to the production of CCL2 that promoted macrophage recruitment. Inhibition of CCL2 or IL6 broke this loop and reduced macrophage migration and mesenchymal CTC-mediated metastasis, respectively. Conclusions Our data indicates that TAMs induce EMT program to enhance CRC migration, invasion, and CTC-mediated metastasis by regulating the JAK2/STAT3/miR-506-3p/FoxQ1 axis, which in turn leads to the production of CCL2 that promote macrophage recruitment, revealing a new cross-talk between immune cells and tumor cells in CRC microenvironment. Electronic supplementary material The online version of this article (10.1186/s12943-019-0976-4) contains supplementary material, which is available to authorized users.
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                Author and article information

                Contributors
                zhangmeihua81@hotmail.com
                jintf@ybu.edu.cn
                Journal
                J Cell Mol Med
                J Cell Mol Med
                10.1111/(ISSN)1582-4934
                JCMM
                Journal of Cellular and Molecular Medicine
                John Wiley and Sons Inc. (Hoboken )
                1582-1838
                1582-4934
                13 November 2022
                December 2022
                : 26
                : 23 ( doiID: 10.1111/jcmm.v26.23 )
                : 5872-5886
                Affiliations
                [ 1 ] Department of Pathology and Cancer Research Center Yanbian University Medical College Yanji China
                [ 2 ] Key Laboratory of the Science and Technology Department of Jilin Province Yanji China
                [ 3 ] Department of Health Examination Centre Yanbian University Hospital Yanji China
                [ 4 ] Department of radiology Yanbian University Hospital Yanji China
                Author notes
                [*] [* ] Correspondence

                Tiefeng Jin, Department of Pathology and Cancer Research Center, Yanbian University Medical College, Gong Yuan Road No.977, Yanji 133002, China.

                Email: jintf@ 123456ybu.edu.cn

                Meihua Zhang, Department of Health Examination Centre, Yanbian University Hospital, Yanji 133002, China.

                Email: zhangmeihua81@ 123456hotmail.com

                Author information
                https://orcid.org/0000-0003-2386-922X
                https://orcid.org/0000-0003-1117-886X
                Article
                JCMM17610 JCMM-03-2022-118.R2
                10.1111/jcmm.17610
                9716221
                36372977
                4f9ab9b6-c7e4-4638-914a-93a9ca0aa4f9
                © 2022 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 12 October 2022
                : 23 March 2022
                : 21 October 2022
                Page count
                Figures: 7, Tables: 0, Pages: 15, Words: 6101
                Funding
                Funded by: National Natural Science Foundation of China , doi 10.13039/501100001809;
                Award ID: 81960554
                Award ID: 82060554
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                December 2022
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.2.1 mode:remove_FC converted:02.12.2022

                Molecular medicine
                emt,nsclc,pd‐l1,stat3,tam/m2
                Molecular medicine
                emt, nsclc, pd‐l1, stat3, tam/m2

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