Macrophage Development Rewritten Macrophages provide protection against a wide variety of infections and critically shape the inflammatory environment in many tissues. These cells come in many flavors, as determined by differences in gene expression, cell surface phenotype and specific function. Schulz et al. (p. 86, published online 22 March) investigated whether adult macrophages all share a common developmental origin. Immune cells, including most macrophages, are widely thought to arise from hematopoietic stem cells (HSCs), which require the transcription factor Myb for their development. Analysis of Myb-deficient mice revealed that a population of yolk-sac–derived, tissue-resident macrophages was able to develop and persist in adult mice in the absence of HSCs. Importantly, yolk sac–derived macrophages also contributed substantially to the tissue macrophage pool even when HSCs were present. In mice, a population of tissue-resident macrophages arises independently of bone marrow–derived stem cells. Macrophages and dendritic cells (DCs) are key components of cellular immunity and are thought to originate and renew from hematopoietic stem cells (HSCs). However, some macrophages develop in the embryo before the appearance of definitive HSCs. We thus reinvestigated macrophage development. We found that the transcription factor Myb was required for development of HSCs and all CD11bhigh monocytes and macrophages, but was dispensable for yolk sac (YS) macrophages and for the development of YS-derived F4/80bright macrophages in several tissues, such as liver Kupffer cells, epidermal Langerhans cells, and microglia—cell populations that all can persist in adult mice independently of HSCs. These results define a lineage of tissue macrophages that derive from the YS and are genetically distinct from HSC progeny.

A lineage of myeloid cells independent of Myb and hematopoietic stem cells

The dynamic interactions of cancer cells with their microenvironment consisting of stromal cells (cellular part) and extracellular matrix (ECM) components (non-cellular) is essential to stimulate the heterogeneity of cancer cell, clonal evolution and to increase the multidrug resistance ending in cancer cell progression and metastasis. The reciprocal cell-cell/ECM interaction and tumor cell hijacking of non-malignant cells force stromal cells to lose their function and acquire new phenotypes that promote development and invasion of tumor cells. Understanding the underlying cellular and molecular mechanisms governing these interactions can be used as a novel strategy to indirectly disrupt cancer cell interplay and contribute to the development of efficient and safe therapeutic strategies to fight cancer. Furthermore, the tumor-derived circulating materials can also be used as cancer diagnostic tools to precisely predict and monitor the outcome of therapy. This review evaluates such potentials in various advanced cancer models, with a focus on 3D systems as well as lab-on-chip devices.

https://link.springer.com/content/pdf/10.1186/s12964-020-0530-4.pdf

Tumor microenvironment complexity and therapeutic implications at a glance.

Macrophages play an important role in cancer development and metastasis. Proinflammatory M1 macrophages can phagocytose tumor cells, while anti-inflammatory M2 macrophages such as tumor-associated macrophages (TAMs) promote tumor growth and invasion. Modulating the tumor immune microenvironment through engineering macrophages is efficacious in tumor therapy. M1 macrophages target cancerous cells and, therefore, can be used as drug carriers for tumor therapy. Herein, the strategies to engineer macrophages for cancer immunotherapy, such as inhibition of macrophage recruitment, depletion of TAMs, reprograming of TAMs, and blocking of the CD47-SIRPα pathway, are discussed. Further, the recent advances in drug delivery using M1 macrophages, macrophage-derived exosomes, and macrophage-membrane-coated nanoparticles are elaborated. Overall, there is still significant room for development in macrophage-mediated immune modulation and macrophage-mediated drug delivery, which will further enhance current tumor therapies against various malignant solid tumors, including drug-resistant tumors and metastatic tumors.

Engineering Macrophages for Cancer Immunotherapy and Drug Delivery.

Tumor-associated macrophages (TAMs) as immune cells within the tumor microenvironment have gained much interests as basic science regarding their roles in tumor progression unfolds. Better understanding of their polarization into pro-tumoral phenotype to promote tumor growth, tumor angiogenesis, immune evasion, and tumor metastasis has prompted various studies to investigate their clinical significance as a biomarker of predictive and prognostic value across different cancer types. Yet, the methodologies to investigate the polarization phenomena in solid tumor tissue vary. Nonetheless, quantifying the ratio of M1 to M2 TAMs has emerged to be a prevailing parameter to evaluate this polarization phenomena for clinical application. This mini-review focuses on recent studies exploring clinical significance of M1/M2 TAM ratio in human cancer tissue and critically evaluates the technicalities and challenges in quantifying this parameter for routine clinical practice. Immunohistochemistry appears to be the preferred methodology for M1/M2 TAM evaluation as it is readily available in clinical laboratories, albeit with certain limitations. Recommendations are made to standardize the quantification of TAMs for better transition into clinical practice and for better comparison among studies in various populations of patients and cancer types.

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Evaluating the Polarization of Tumor-Associated Macrophages Into M1 and M2 Phenotypes in Human Cancer Tissue: Technicalities and Challenges in Routine Clinical Practice

Tumor microenvironment and epithelial mesenchymal transition as targets to overcome tumor multidrug resistance

Tumor metastasis is a major contributor to the death of cancer patients. It is driven not only by the intrinsic alterations in tumor cells, but also by the implicated cross-talk between cancer cells and their altered microenvironment components. Tumor-associated macrophages (TAMs) are the key cells that create an immunosuppressive tumor microenvironment (TME) by producing cytokines, chemokines, growth factors, and triggering the inhibitory immune checkpoint proteins release in T cells. In doing so, TAMs exhibit important functions in facilitating a metastatic cascade of cancer cells and, meanwhile, provide multiple targets of certain checkpoint blockade immunotherapies for opposing tumor progression. In this article, we summarize the regulating networks of TAM polarization and the mechanisms underlying TAM-facilitated metastasis. Based on the overview of current experimental evidence dissecting the critical roles of TAMs in tumor metastasis, we discuss and prospect the potential applications of TAM-focused therapeutic strategies in clinical cancer treatment at present and in the future.

/pdf/tumor-associated-macrophages-in-tumor-metastasis-biological-2fyfdk1mmg.pdf

Tumor-associated macrophages in tumor metastasis: biological roles and clinical therapeutic applications

Epithelial-mesenchymal transition (EMT) has been associated with the angiogenesis and oncogenic phenotypes of multiple malignant tumors including bladder cancer (BCa). Circular RNAs (circRNAs) are recognized as crucial regulators in the EMT. This study aims to illustrate the possible role of circular RNA_0000658 (circ_0000658) in BCa and the underlying molecular mechanism.The expression of circ_0000658, microRNA (miR)-498, and high mobility group AT-hook 2 (HMGA2) was assessed in cancer and adjacent normal tissue collected from BCa patients and human BCa cell lines (MGH-U3, T24, 5637 and SW780). BCa cells were transduced with a series of overexpression or shRNA plasmids to clarify the function of circ_0000658 and miR-498 on the oncogenic phenotypes and EMT of BCa cells. Further, we established nude mice xenografted with BCa cells to validate the roles of circ_0000658 on tumor growth in vivo.Circ_0000658 was highly expressed in BCa tissue samples and cell lines, which indicated a poor prognosis of BCa patients. Circ_0000658 competitively bound to miR-498 and thus restricted miR-498 expression. Meanwhile, circ_0000658 weakened the binding of miR-498 to the target gene HMGA2 and upregulated the HMGA2 expression. Circ_0000658 elevation or miR-498 knockdown augmented oncogenic phenotypes and EMT of BCa cells, corresponding to a reduction in the expression of β-catenin and E-cadherin as well as an increase in the expression of N-cadherin, Slug, Snail, ZEB1 and Twist. Inhibition of HMGA2 reversed the effects of circ_0000658 overexpression on tumor growth in vivo.Altogether, our study uncovered the tumor-promoting role of circ_0000658 in BCa via the miR-498/HMGA2 axis. 

/pdf/circ-0000658-knockdown-inhibits-epithelial-mesenchymal-1vtyr206.pdf

Circ_0000658 knockdown inhibits epithelial-mesenchymal transition in bladder cancer via miR-498-induced HMGA2 downregulation

Objective Thyroid cancer (TC) is one of the most common malignant tumours of the endocrine system. Thyroid-stimulating hormone (TSH) is known as being a risk factor for TC, but other thyroid-related hormones are inconsistently associated with TC. The purpose of this study was to comprehensively evaluate the relationships between thyroid-related hormones and the risk of TC. Methods This study utilized searches of PubMed, Embase, Web of Science and Cochrane library up to the date of March 31st, 2022. Additionally, we performed a systematic review of related original studies combining overall and dose–response meta-analyses. Results A total of 30, 5 and 7 articles were included in the meta-analyses of TSH, Free triiodothyronine (FT3), free thyroxine (FT4) and TC risk with 58437, 6813 and 7118 participants respectively. An increased risk of TC was associated with high TSH exposure (OR=1.28, 95% CI: 1.19-1.37, P < 0.001) in the overall meta-analysis. For every 1 mU/L increase in TSH, the risk of TC increased by 16%. However, in those studies that used healthy subjects as controls, the association was not statistically significant(P=0.62). Additionally, high serum FT3 demonstrated a reduced risk of TC, with a combined OR of 0.86 in the fixed-effect model (95% CI: 0.81–0.90, P < 0.001). In addition, a statistically significant increase in TC risk was found when FT4 concentrations reached a certain threshold (approximately 2.2 ng/dL) in the dose-response meta-analysis. Conclusions Significant associations between thyroid-related hormones and the risk of TC were found in this study. Further research is needed to understand the underlying mechanisms.

/pdf/the-associations-between-thyroid-related-hormones-and-the-10rzk5z2.pdf

The associations between thyroid-related hormones and the risk of thyroid cancer: An overall and dose-response meta-analysis

Immune checkpoint inhibitor (ICI) treatment has dramatically revolutionized the landscape of therapeutic approaches in multiple cancers, particularly, non-small-cell lung cancer (NSCLC). With the increasing use of programmed death-1 (PD-1) inhibitors in the clinic, the emerging toxicity profile presents a novel learning curve for clinicians. Here we report the first case of an NSCLC patient displaying sarcoid/granulomatous-like reaction (SLR, also known as GLR) in the liver during an anti-PD-1 therapy which showed efficacious response of complete regression. Also, this is the first report describing the SLR induced by toripalimab, a novel PD-1 inhibitor. Given this kind of hepatic findings can be easily mistaken as metastasis, even resulting in premature use of second-line treatments. In particular, we briefly review the clinical features of all those cases reporting sarcoidosis and SLRs manifested on different organs during anti-PD-(L)1 therapy. We anticipate that these clinical cases would help to alert the attention of clinicians that SLRs, as a rare immune-related adverse event (irAE), is manageable and that histopathological analysis is necessary before interpreting it as disease progression.

Yuxin Lin

Papers

Tumor-associated macrophages in tumor metastasis: biological roles and clinical therapeutic applications

Circ_0000658 knockdown inhibits epithelial-mesenchymal transition in bladder cancer via miR-498-induced HMGA2 downregulation

The associations between thyroid-related hormones and the risk of thyroid cancer: An overall and dose-response meta-analysis

Case Report: Hepatic Sarcoid-Like Reaction Associated With Checkpoint Inhibition in a NSCLC Patient and a Literature Review