With the development of immunotherapy and increased implementation of precision medicine approaches, pathologists need to provide more than just a diagnosis or margin status. The information obtained by reviewing hematoxylin and eosin-stained tissue slides with brightfield microscopy is limited. Traditional Methods for Phenotyping Immune Cells In Situįor more than 100 years, light microscopy has been the traditional method for pathologists to evaluate tissue specimens. Finally, recent investigations of TAMs in HCC progression are described.Ģ.1. We also suggest how each may contribute to the development of TAM-targeting drugs and personalized medicine. The basic principles of each technique are outlined, along with the advantages and disadvantages of each platform. In this review, emerging platforms that can characterize intrahepatic macrophages in situ in human liver tissue will be discussed. TAMs are a promising target for immunotherapy, and accurate characterization will be necessary for successful implementation of precision medicine approaches. Therefore, other methods that can study the complex hepatic microenvironment in situ in human liver tissue may be better approaches. Despite various techniques for isolating and characterizing TAMs, their study is challenging because of the following: (1) isolation of the cells from human liver tissue is laborious, (2) macrophages transform their phenotype upon manipulation, and (3) in vitro and mouse model systems poorly replicate the TME, and chronic disease observed in humans. The profound influence of TAMs on tumor progression is confirmed by a growing body of data indicating that agents targeting TAMs are critical for optimal HCC therapy. Preclinical studies have found a strong correlation between macrophages infiltrating the TME and poor prognosis. The prevailing view is that TAMs in HCC are involved in immunosuppression, angiogenesis, epithelial-mesenchymal transition, cytokine secretion, enhancement of metastasis, and prolongation of stemness. The specific role of TAMs in promotion of HCC is controversial and poorly understood since most studies to date rely upon traditional in vitro and in vivo animal models (e.g., mouse models) that poorly replicate the tumor microenvironment (TME) in humans. Tumor-associated macrophages (TAMs) are a critical subpopulation that can promote tumor growth within the hepatic microenvironment and unique phenotypes with diverse functional properties have been described. The hepatic microenvironment in HCC is composed of a heterogenous population of cells with distinct genetic and phenotypic properties and various effects on tumor progression. So far, the implementation of new diagnostic strategies and therapeutic regimens has not yet resulted in a significant reduction in mortality, as HCC is the second most lethal tumor, outranked only by pancreatic cancer, in the United States. The mortality rate from HCC is increasing faster than any other cancer in the United States and is also a leading cause of cancer deaths globally, accounting for more than 700,000 deaths each year. Hepatocellular carcinoma (HCC) is the most common primary liver malignancy in the United States and worldwide. This review describes the workflow of each platform, summarizes recent research using these approaches, and explains the advantages and limitations of each. Macrophages can also be specifically targeted and analyzed, enabling quantification of both protein and gene expression within specific cell phenotypes, including TAMs. Newer spatial profiling platforms allow for detection of numerous protein targets, in combination with whole transcriptome analysis, in a single liver biopsy tissue section. In cancer research, these platforms enable characterization of immune cell phenotypes and expression of potential therapeutic targets, such as PDL-1 and CTLA-4. These technologies, such as multispectral imaging (e.g., Vectra Polaris), mass cytometry by time-of-flight (e.g., Fluidigm CyTOF), cycling of fluorochromes (e.g., Akoya Biosciences CODEX/PhenoCycler-Fusion, Bruker Canopy, Lunaphore Comet, and C圜IF) and digital spatial profiling or transcriptomics (e.g., GeoMx or Visium, Vizgen Merscope) are being utilized to accurately assess the complex cellular network within the tissue microenvironment. State-of-the-art methods provides new strategies to study TAMs without losing the context of tissue architecture and spatial relationship with neighboring cells. Cell isolation causes activation and phenotypic changes that may not represent their actual biology and function in situ. Most studies rely on platforms that remove intrahepatic macrophages from the microenvironment prior to evaluation. The role of tumor-associated macrophages (TAMs) in the pathogenesis of hepatocellular carcinoma (HCC) is poorly understood.
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