Landscape and perspectives of macrophage -targeted cancer therapy in clinical trials

Wang, Shuhang; Yang, Yuqi; Ma, Peiwen; Huang, Huiyao; Tang, Qiyu; Miao, Huilei; Fang, Yuan; Jiang, Ning; Li, Yandong; Zhu, Qi; Tao, Wei; Zha, Yan; Li, Ning

doi:10.1016/j.omto.2022.02.019

Cited by 37 publications

(33 citation statements)

References 82 publications

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“…During the past decade, the explosive growth in macrophage-targeted therapy indicates that the TAM-targeted therapy is an effective antitumor strategy, especially as a complementary strategy in combination with conventional chemotherapy, radiotherapy, or immunotherapy. Most of the preclinical studies and clinical trials have been based on the therapeutic strategies according to their different mechanisms, including those that inhibit mononuclear macrophage recruitment, those that deplete TAMs, and those that reprogram TAMs [ 176 , 177 ]. However, clinical trials specifically designed to modulate or interfere with the self-renewal of TAMs are lacking.…”

Section: Discussionmentioning

confidence: 99%

Self-Renewal of Macrophages: Tumor-Released Factors and Signaling Pathways

et al. 2022

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Macrophages are the most abundant immune cells of the tumor microenvironment (TME) and have multiple important functions in cancer. During tumor growth, both tissue-resident macrophages and newly recruited monocyte-derived macrophages can give rise to tumor-associated macrophages (TAMs), which have been associated with poor prognosis in most cancers. Compelling evidence indicate that the high degree of plasticity of macrophages and their ability to self-renew majorly impact tumor progression and resistance to therapy. In addition, the microenvironmental factors largely affect the metabolism of macrophages and may have a major influence on TAMs proliferation and subsets functions. Thus, understanding the signaling pathways regulating TAMs self-renewal capacity may help to identify promising targets for the development of novel anticancer agents. In this review, we focus on the environmental factors that promote the capacity of macrophages to self-renew and the molecular mechanisms that govern TAMs proliferation. We also highlight the impact of tumor-derived factors on macrophages metabolism and how distinct metabolic pathways affect macrophage self-renewal.

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Section: Discussionmentioning

confidence: 99%

Self-Renewal of Macrophages: Tumor-Released Factors and Signaling Pathways

et al. 2022

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“…Although immune checkpoint blockers (ICBs), which primarily target cytotoxic T lymphocytes, are widely used in current clinical practice ( 40 , 41 ), TAMs and DCs have also been favored and explored in recent decades. A variety of therapeutic strategies targeting TAMs and DCs are being tested in basic researches and clinical trials ( 42 , 43 , 44 ), for example, inhibiting mononuclear macrophage recruitment, TAM depletion and inhibition of activation, reprogramming TAMs and DC-based cancer vaccines. Correspondingly, a variety of relevant molecules are being targeted, for instance, blockade of CD47 to enhance the phagocytotic abilities of antigen-presenting cells, inhibition of phosphoinositide 3-kinase γ (PI3Kγ) to interrupt M2 polarization, and Toll-like receptor (TLR) agonists to induce M1 polarization.…”

Section: Discussionmentioning

confidence: 99%

EPSTI1 as an immune biomarker predicts the prognosis of patients with stage III colon cancer

Wang

Cheng²,

Zeng³

et al. 2022

Front. Immunol.

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ObjectiveThe poor prognosis and heterogeneity of stage III colon cancer (CC) suggest the need for more prognostic biomarkers. The tumor microenvironment (TME) plays a crucial role in tumor progression. We aimed to explore novel immune infiltration-associated molecules that serve as potential prognostic and therapeutic targets.MethodsTME immune scores were calculated using “TMEscore” algorithm. Differentially expressed genes between the high and low TME immune score groups were identified and further investigated through a protein-protein interaction network and the Molecular Complex Detection algorithm. Cox regression, meta-analysis and immunohistochemistry were applied to identify genes significantly correlated with relapse-free survival (RFS). We estimated immune infiltration using three different algorithms (TIMER 2.0, CIBERSORTx, and TIDE). Single-cell sequencing data were processed by Seurat software.ResultsPoor RFS was observed in the low TME immune score groups (log-rank P < 0.05). EPSTI1 was demonstrated to be significantly correlated with RFS (P < 0.05) in stage III CC. Meta-analysis comprising 547 patients revealed that EPSTI1 was a protective factor (HR = 0.79, 95% CI, 0.65-0. 96; P < 0.05)). More immune infiltrates were observed in the high EPSTI1 group, especially M1 macrophage and myeloid dendritic cell infiltration (P < 0.05).ConclusionThe TME immune score is positively associated with better survival outcomes. EPSTI1 could serve as a novel immune prognostic biomarker for stage III CC.

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“…Tumor-infiltrating M φ s (TAMs) mostly take on an M2-like phenotype and contribute to immune escape, allowing the transformation of neoplastic cells. Herewith, changing M2 M φ s toward M1 M φ s is one of the prospective aims of cancer immunotherapy [ 30 ]. Based on TCGA database, we found a close association of PX targets with the survival probability in patients with CRC, as well as with TAM infiltrating, which corroborates the therapeutic value of PX in the clinic.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological Mechanism of Pingxiao Formula against Colorectal Cancer

Wang

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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Colorectal cancer (CRC) is the most common cancer worldwide and develops due to a broad range of causative factors. Pingxiao (PX) formula and Xihuang (XH) formula are two commonly used drugs to treat CRC, especially as an alternative therapy for those patients who could not suffer surgery, chemotherapy, or immunotherapy, namely, elder or advanced CRC patients. However, the pertinent pharmacological mechanisms are still elusive. The investigation was designed to explain the pharmacological mechanisms of the PX formula. A murine model of CRC was established by injecting CT26.WT cells into the caecum of 4-week-old male Balb/c mice, following PX or XH treatment for 30 days. Network pharmacology analysis combined with weighted gene coexpression network analysis (WGCNA) predicted the pharmacological mechanisms and therapeutic value. High-throughput 16S rRNA sequencing determined the alterations in the gut microbiota communities. Western blotting, immunofluorescence, and flow cytometry examined the influence of PX on the tumor microenvironment (TME). Injection of CT26.WT-induced CRC in Balb/c mice was markedly attenuated by PX treatment. Compared with XH administration, PX exhibited a stronger antitumor effect, such as smaller tumor volume, lower interleukin 17 (IL-17), IL-6 and tumor necrosis factor-alpha (TNFα) serum levels, and higher interferon-gamma (IFN-γ) concentration. Network pharmacology analysis demonstrated that both PX and XH targets were enriched in cancers and inflammatory responses. RNA sequencing confirmed that PX treatment induced cancer cell apoptosis and inhibited inflammatory reactions within the tumor. Moreover, the PX formula considerably restored homeostasis of the gut microbiota, which was not observed in the XH group. PX targets, those associated with the survival probability of CRC patients, correlated with macrophage (Mφ) infiltration, which presented an independent risk factor for the CRC outcome. PX treatment promoted the transition of alternatively activated Mφs (M2 Mφs) to classically activated Mφs (M1 Mφs). Moreover, the peritoneal Mφs from the PX group inhibited the migration of CW26.WT cells, as evidenced by the wound healing experiment and transwell assay, which was consistent with the decreased expression of the vascular endothelial growth factor (VEGF). Furthermore, the coculturing system confirmed that PX-treated Mφs suppressed colorectal tumor-derived organoid proliferation. PX formula exhibits a potential antitumor effect against CRC by suppressing the colonization of pathological microorganisms, reshaping Mφ effector functions and hence inhibiting cancer cell proliferation.

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Landscape and perspectives of macrophage -targeted cancer therapy in clinical trials

Cited by 37 publications

References 82 publications

Self-Renewal of Macrophages: Tumor-Released Factors and Signaling Pathways

Self-Renewal of Macrophages: Tumor-Released Factors and Signaling Pathways

EPSTI1 as an immune biomarker predicts the prognosis of patients with stage III colon cancer

Pharmacological Mechanism of Pingxiao Formula against Colorectal Cancer

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