Blockade of CCL2 enhances immunotherapeutic effect of anti-PD1 in lung cancer

Wang, Yue; Zhang, Xiaokai; Yang, Liangliang; Xue, Jiajia; Hu, Guangrui

doi:10.1016/j.jbo.2018.01.002

Cited by 68 publications

(41 citation statements)

References 33 publications

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“…Anti-CCL2 treatment inhibits the expression of arginase 1 and iNOS, thereby reducing G-MDSC and M-MDSC in and around the tumor. Combination therapy can increase CD4 + and CD8 + T cell infiltration and prolong the survival of tumor-bearing mice [169]. Furthermore, the inhibition of HDAC6 significantly reduces HLA-DR-Low/CD11b + CD33 + MDSCs in the tumor microenvironment [156].…”

Section: Combination Therapeutic Strategy To Enhance T Immune Cell Fumentioning

confidence: 99%

Predictive biomarkers and mechanisms underlying resistance to PD1/PD-L1 blockade cancer immunotherapy

et al. 2020

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Immune checkpoint blockade targeting PD-1/PD-L1 has promising therapeutic efficacy in a variety of tumors, but resistance during treatment is a major issue. In this review, we describe the utility of PD-L1 expression levels, mutation burden, immune cell infiltration, and immune cell function for predicting the efficacy of PD-1/PD-L1 blockade therapy. Furthermore, we explore the mechanisms underlying immunotherapy resistance caused by PD-L1 expression on tumor cells, T cell dysfunction, and T cell exhaustion. Based on these mechanisms, we propose combination therapeutic strategies. We emphasize the importance of patient-specific treatment plans to reduce the economic burden and prolong the life of patients. The predictive indicators, resistance mechanisms, and combination therapies described in this review provide a basis for improved precision medicine.

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Section: Combination Therapeutic Strategy To Enhance T Immune Cell Fumentioning

confidence: 99%

Predictive biomarkers and mechanisms underlying resistance to PD1/PD-L1 blockade cancer immunotherapy

et al. 2020

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“…Wang et al showed that MDSC subsets had a positive correlation with CCL2. In addition, combination treatment with a CCL2 antagonist and anti-PD1 antibody enhanced CD4 + and CD8 + T cell infiltration, as well as the production of IFNγ, and increased the survival time of tumor-bearing mice [105]. KRAS mutations, known as oncogenic driver mutations, have been detected in 20~40% of adenocarcinomas and in 3~6% of squamous cell carcinomas [132].…”

Section: Increased Immune Checkpoint Inhibitor Efficacymentioning

confidence: 99%

Myeloid-derived suppressor cells—new and exciting players in lung cancer

et al. 2020

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Lung cancer (LC) is the leading cause of cancer-related death worldwide due to its late diagnosis and poor outcomes. As has been found for other types of tumors, there is increasing evidence that myeloid-derived suppressor cells (MDSCs) play important roles in the promotion and progression of LC. Here, we briefly introduce the definition of MDSCs and their immunosuppressive functions. We next specifically discuss the multiple roles of MDSCs in the lung tumor microenvironment, including those in tumor growth and progression mediated by inhibiting antitumor immunity, and the associations of MDSCs with a poor prognosis and increased resistance to chemotherapy and immunotherapy. Finally, we also discuss preclinical and clinical treatment strategies targeting MDSCs, which may have the potential to enhance the efficacy of immunotherapy.

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“…Recent studies showed that the CCL2/CCR2 axis plays a vital role in the brotic formation in some diseases, including pulmonary brosis, renal brosis and nonalcoholic liver brosis, in addition to chemotactic macrophage in ltration [27,44,45]. It is found that CCL2/CCR2 axis was closely related to aggregation of myeloid-derived inhibitory cells (MDSCs) and inhibition of T cell function in pulmonary brosis and lung cancer [46]. The proportions of CD11C + CD206 + and CCR2 + macrophages in adipose tissues highly elevated in patients with NASH compared to healthy controls and to patients with fatty liver and CCR2 + macrophages were also correlated with NASH severity (44).…”

Section: Disscussionmentioning

confidence: 99%

Activated Hepatic Stellate Cells Induce Infiltration and Formation of CD163+ Macrophages via CCL2/CCR2 Pathway

Shi

Zheng

Jiang

et al. 2020

Preprint

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Background: Growing evidence indicates that activated hepatic stellate cells (aHSCs) play unexpected roles in regulating immune cells’ function during liver fibrosis. Macrophages feature with inducible plasticity according to the circumstances while patrol for potential pathogens. However, studies seldom investigate whether and how the aHSCs regulate the phenotype and function of macrophages during liver fibrosis. Methods: 96 patients with different stages of liver fibrosis were involved in our study. Metavir score system was used to evaluate the degree of fibrosis. The expression of hepatic CCL2 and CD163 were detected by immunohistochemistry, and the relationship among CD163, CCL2, and fibrosis scores were explored. We co-cultured the aHSCs and THP-1-derived M0-type macrophages (M0MФ) to observe whether aHSCs modulate the expression of CD163 on macrophages in vitro. Furthermore, we treated the M0MФ with aHSCs’ supernatant and investigated the production of CCL2 in aHSCs by ELISA and immunofluorescence assay. To explore whether CCL2/CCR2 axis plays a crucial role in macrophage phenotypic changes during liver fibrosis, we used recombinant CCL2 and its specific receptor antagonist. Moreover, we employed LX2 system to confirm our results. Results: We found that hepatic M2 macrophages (CD163+) infiltration increased in different stages of liver fibrosis (F0-1: 34.95±18.12; F2-3: 77.57±32.48; F4: 99.62±40.84, F0-1 vs. F2-3, P<0.001; F2-3 vs. F4, P=0.074). After in vitro co-cultured with aHSCs, the macrophages expressed higher levels of CD163 (29.5±6.1% vs. 2.7±1.1%) as well as CD206 (28.0±4.2% vs. 2.4±1.2%) compared with the control. Then we found aHSC supernatant up-regulated the expression of CD163 (26.1±2.8%) and CD206 (25.8±3.8%) on macrophages independently. We noted aHSCs’ supernatant contained a high level of CCL2, which increased dramatically while TGF-β stimulation. Meanwhile, CCL2 staining score increased with the progress of fibrosis ( N: 23.26±13.85; F1: 4 8.56±19.18; F2: 58.25±16.24; F3: 81.32±18.48; F4: 110.93±24.75). Intriguingly, CCL2 significantly up-regulated the expression of CD163 (27.6±7.0%) and CD206 (26.5±5.1%) on macrophages besides inducing their aggregation. Results were confirmed with LX2 co-culture system. Conclusions: (1) The expression of M2 macrophage marker CD163 increased significantly during the progress of liver fibrosis and associated with fibrosis severity. (2) AHSCs can recruit macrophages and induce their M2 phenotypic transformation through CCL2/CCR2 pathway.

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Blockade of CCL2 enhances immunotherapeutic effect of anti-PD1 in lung cancer

Cited by 68 publications

References 33 publications

Predictive biomarkers and mechanisms underlying resistance to PD1/PD-L1 blockade cancer immunotherapy

Predictive biomarkers and mechanisms underlying resistance to PD1/PD-L1 blockade cancer immunotherapy

Myeloid-derived suppressor cells—new and exciting players in lung cancer

Activated Hepatic Stellate Cells Induce Infiltration and Formation of CD163+ Macrophages via CCL2/CCR2 Pathway

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