Immunosuppressive tumor-associated macrophages expressing interlukin-10 conferred poor prognosis and therapeutic vulnerability in patients with muscle-invasive bladder cancer

Xu, Yijia; Zeng, Han; Jin, Kaifeng; Liu, Zhaopei; Zhu, Yu; Xu, Liang; Wang, Zewei; Chang, Yuan; Xu, Jiejie

doi:10.1136/jitc-2021-003416

Cited by 49 publications

(36 citation statements)

References 47 publications

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“…High infiltrations of IL-10 + TAMs cause immune effector cells such as CD8 + T cells and NK cells to be fatigued or dysfunctional, depriving them of their active role in anti-tumor immune responses. IL-10 also suppresses cytotoxic T cell responses by inducing monocytes to express the co-stimulatory molecule PD-L1 and upregulating immune checkpoints, such as CTLA-4, TIM-3, and LAG-3 [ 89 , 90 ]. Serum IL-10 levels have been found to positively correlate with tumor progression; moreover, studies have revealed that IL-10 + TAMs act as a signaling molecule that promotes immune evasion in breast, gastric, and bladder cancers, negatively correlating with overall patient survival and recurrence-free survival [ 90 – 92 ].…”

Section: Mechanisms Of Tumor Progression Mediated By Macrophagesmentioning

confidence: 99%

“…IL-10 also suppresses cytotoxic T cell responses by inducing monocytes to express the co-stimulatory molecule PD-L1 and upregulating immune checkpoints, such as CTLA-4, TIM-3, and LAG-3 [ 89 , 90 ]. Serum IL-10 levels have been found to positively correlate with tumor progression; moreover, studies have revealed that IL-10 + TAMs act as a signaling molecule that promotes immune evasion in breast, gastric, and bladder cancers, negatively correlating with overall patient survival and recurrence-free survival [ 90 – 92 ]. In addition, Toll-like receptor 4 (TLR4) stimulates IL-10 secretion through M2 macrophages [ 93 ], and therefore, TLR4 may also be a key signal that promotes alterations in the TME.…”

Section: Mechanisms Of Tumor Progression Mediated By Macrophagesmentioning

confidence: 99%

“…For example, cyclophosphamide enhances the production of proinflammatory cytokines (IL-12 and -6) and inhibits the secretion of protumor M2-related cytokines, including but not limited to IL-10. Cyclophosphamide-based immunotherapy for solid tumors has long been used in the clinic and several clinical trials are underway [ 90 ].…”

Section: Strategies For Targeting Macrophages In the Treatment Of Sol...mentioning

confidence: 99%

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Targeting macrophages: a novel treatment strategy in solid tumors

Liu

Song

et al. 2022

J Transl Med

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In the tumor microenvironment (TME), tumor-associated macrophages (TAMs) are the most abundant immune cells, which act as a key regulator in tumorigenesis and progression. Increasing evidence have demonstrated that the TME alters the nature of macrophages to maintain dynamic tissue homeostasis, allowing TAMs to acquire the ability to stimulate angiogenesis, promote tumor metastasis and recurrence, and suppress anti-tumor immune responses. Furthermore, tumors with high TAM infiltration have poor prognoses and are resistant to treatment. In the field of solid tumor, the exploration of tumor-promoting mechanisms of TAMs has attracted much attention and targeting TAMs has emerged as a promising immunotherapeutic strategy. Currently, the most common therapeutic options for targeting TAMs are as follows: the deletion of TAMs, the inhibition of TAMs recruitment, the release of phagocytosis by TAMs, and the reprogramming of macrophages to remodel their anti-tumor capacity. Promisingly, the study of chimeric antigen receptor macrophages (CAR-Ms) may provide even greater benefit for patients with solid tumors. In this review, we discuss how TAMs promote the progression of solid tumors as well as summarize emerging immunotherapeutic strategies that targeting macrophages.

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Section: Mechanisms Of Tumor Progression Mediated By Macrophagesmentioning

confidence: 99%

Section: Mechanisms Of Tumor Progression Mediated By Macrophagesmentioning

confidence: 99%

Section: Strategies For Targeting Macrophages In the Treatment Of Sol...mentioning

confidence: 99%

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Targeting macrophages: a novel treatment strategy in solid tumors

Liu

Song

et al. 2022

J Transl Med

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“…The survival of subtype 3 is significantly worse than subtype 2 may be caused by the difference in M2 macrophages infiltrates (p ≤ 0.01, Figure S6A). Studies have shown that macrophages with local infiltration can undergo M2 type polarization in the tumor microenvironment, thereby exerting immunosuppressive effects and promoting intratumoral angiogenesis, tumor proliferation, invasion, and invasion metastasis (30,31).In addition, subtypes 3 patients showed higher angiogenesis (Angiogenesis, p ≤ 0.001), pan-fibroblast TGF-b(Pan-F-TBRs, p ≤ 0.0001), and epithelial interstitial transformation (EMT, p ≤ 0.05) (Figure S6B) compared with subtypes 2, suggesting that subtypes 3 patients had more robust pro-cancer activity. which is consistent with a worse prognosis for patients (Figure 2B).…”

Section: Discussionmentioning

confidence: 99%

Lactate: A regulator of immune microenvironment and a clinical prognosis indicator in colorectal cancer

et al. 2022

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Lactate can play an immunosuppressive role in the tumor microenvironment and promote tumor development by recruiting and inducing the activity of immunosuppressive cells and molecules. High lactate concentrations are important for tumor cell metastasis, angiogenesis, and treatment resistance. With the in-depth studies on tumor metabolism, lactate, one of the key factors involved in glycolysis, has been increasing emerged its characteristic clinical value in colorectal cancer (CRC). In this study, lactate genes were screened based on lactate metabolism pathways. Subsequently, the lactate subtypes were determined by clustering and analysis of the subtypes at all levels, including immune checkpoints, immune infiltration, and clinical characteristics, which revealed the biological significance of lactate metabolism in CRC. Subtype-based differential gene analysis resulted in a lactate score, which stratifies the prognosis of CRC. We discovered that 27 lactate genes and 61 lactate-phenotype genes are associated with immune cell infiltration and have a significant prognostic efficacy. The CRC patients were clustered into four subtypes and five clusters, based on lactate genes and lactate-phenotype genes, respectively. There are significant differences in survival time and activities of hallmark pathways, namely immune-related signatures and chemokines, among these subtypes and clusters. Particularly, cluster 2 and subtype 1 have significantly higher lactate scores than that of the others. In conclusion, lactate score is an independent prognostic factor for cancer that can be used as a clinical guide for predicting CRC progression and as an evaluation factor for the effect of immunotherapy in CRC.

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“…In the TME, the accumulation of cytokines, chemokines, soluble factors, and a mixture of biomolecules in exosomes compromises the immune response during the advanced stages of cancer ( 156 – 158 ). Soluble factors with immunosuppressant activity, such as IL-10, TGF-b, IL-4, IL-6, etc., impair the function of NK cells ( 159 , 160 ) and CTLs ( 161 , 162 ) by inhibiting their effector activity and downregulating the expression of transcripts coding for cytolytic molecules. This cytokine environment induces the differentiation of CD4+ T to Treg cells ( 163 – 165 ) and maintains a stage of dedifferentiation in MDSCs by enhancing the expression of TGF-β and IL-10.…”

Section: Participation Of the Immune Response In Cancermentioning

confidence: 99%

The systemic-level repercussions of cancer-associated inflammation mediators produced in the tumor microenvironment

et al. 2022

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The tumor microenvironment is a dynamic, complex, and redundant network of interactions between tumor, immune, and stromal cells. In this intricate environment, cells communicate through membrane–membrane, ligand–receptor, exosome, soluble factors, and transporter interactions that govern cell fate. These interactions activate the diverse and superfluous signaling pathways involved in tumor promotion and progression and induce subtle changes in the functional activity of infiltrating immune cells.The immune response participates as a selective pressure in tumor development. In the early stages of tumor development, the immune response exerts anti-tumor activity, whereas during the advanced stages, the tumor establishes mechanisms to evade the immune response, eliciting a chronic inflammation process that shows a pro-tumor effect.The deregulated inflammatory state, in addition to acting locally, also triggers systemic inflammation that has repercussions in various organs and tissues that are distant from the tumor site, causing the emergence of various symptoms designated as paraneoplastic syndromes, which compromise the response to treatment, quality of life, and survival of cancer patients. Considering the tumor–host relationship as an integral and dynamic biological system, the chronic inflammation generated by the tumor is a communication mechanism among tissues and organs that is primarily orchestrated through different signals, such as cytokines, chemokines, growth factors, and exosomes, to provide the tumor with energetic components that allow it to continue proliferating. In this review, we aim to provide a succinct overview of the involvement of cancer-related inflammation at the local and systemic level throughout tumor development and the emergence of some paraneoplastic syndromes and their main clinical manifestations. In addition, the involvement of these signals throughout tumor development will be discussed based on the physiological/biological activities of innate and adaptive immune cells. These cellular interactions require a metabolic reprogramming program for the full activation of the various cells; thus, these requirements and the by-products released into the microenvironment will be considered. In addition, the systemic impact of cancer-related proinflammatory cytokines on the liver—as a critical organ that produces the leading inflammatory markers described to date—will be summarized. Finally, the contribution of cancer-related inflammation to the development of two paraneoplastic syndromes, myelopoiesis and cachexia, will be discussed.

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Immunosuppressive tumor-associated macrophages expressing interlukin-10 conferred poor prognosis and therapeutic vulnerability in patients with muscle-invasive bladder cancer

Cited by 49 publications

References 47 publications

Targeting macrophages: a novel treatment strategy in solid tumors

Targeting macrophages: a novel treatment strategy in solid tumors

Lactate: A regulator of immune microenvironment and a clinical prognosis indicator in colorectal cancer

The systemic-level repercussions of cancer-associated inflammation mediators produced in the tumor microenvironment

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