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Simple Summary: Immunotherapy targeting immune checkpoints and stromal cells in the tumor microenvironment is currently one of the most promising directions for tumor therapy. Ongoing studies suggest that CD73 plays an important role in the tumor immune process in certain tumors, however, the exact mechanism is unknown. We aim to fully reveal the prognostic value of CD73 in pan-cancer and its role in tumor immunity through large-scale single-cell and bulk sequencing analysis. We found that high CD73 expression was significantly associated with poor prognosis in many tumors. It is also strongly associated with immune scores, stromal cell infiltration, and immune-related pathways. CD73 can regulate the biological behavior of immune cells in the tumor microenvironment, especially macrophages and T cells. Immunotherapy targeting CD73 has obvious effects, and CD73 may shine as a new immune checkpoint in future tumor immunotherapy. CD73 is essential in promoting tumor growth by prohibiting anti-tumor immunity in many cancer types. While the mechanism remains largely unknown, our paper comprehensively confirmed the onco-immunological characteristics of CD73 in the tumor microenvironment (TME) of pan-cancer. This paper explored the expression pattern, mutational profile, prognostic value, tumor immune infiltration, and response to immunotherapy of CD73 in a continuous cohort of cancers through various computational tools. The co-expression of CD73 on cancer cells, immune cells, and stromal cells in the TME was also detected. Especially, we examined the correlation between CD73 and CD8+ (a marker of T cell), CD68+ (a marker of macrophage), and CD163+ (a marker of M2 macrophage) cells using multiplex immunofluorescence staining of tissue microarrays. CD73 expression is significantly associated with a patient's prognosis and could be a promising predictor of these cancers. High CD73 levels are strongly linked to immune infiltrations, neoantigens, and immune checkpoint expression in the TME. In particular, enrichment signaling pathway analysis demonstrated that CD73 was obviously related to activation pathways of immune cells, including T cells, macrophages, and cancer-associated fibroblasts (CAFs). Meanwhile, single-cell sequencing algorithms found that CD73 is predominantly co-expressed on cancer cells, CAFs, M2 macrophages, and T cells in several cancers. In addition, we explored the cellular communication among 14 cell types in glioblastoma (GBM) based on CD73 expression. Based on the expression of CD73 as well as macrophage and T cell markers, we predicted the methylation and enrichment pathways of these markers in pan-cancer. Furthermore, a lot of therapeutic molecules sensitive to these markers were predicted. Finally, potential anticancer inhibitors, immunotherapies, and gene therapy responses targeting CD73 were identified from a series of immunotherapy cohorts. CD73 is closely linked to clinical prognosis and immune infiltration in many cancers. Targeting CD73-dependent signaling pathways may be a promising therapeutic strategy for future tumor immunotherapy. [ABSTRACT FROM AUTHOR]

The four variables, hypoxia, acidity, high glutathione (GSH) concentration and fast reducing rate (redox) are distinct and varied characteristics of solid tumors compared to normal tissue. These parameters are among the most significant factors underlying the metabolism and physiology of solid tumors, regardless of their type or origin. Low oxygen tension contributes to both inhibition of cancer cell proliferation and therapeutic resistance of tumors; low extracellular pH, the reverse of normal cells, mainly enhances tumor invasion; and dysregulated GSH and redox potential within cancer cells favor their proliferation. In fact, cancer cells under these microenvironmental conditions appreciably alter tumor response to cytotoxic anti-cancer treatments. Recent experiments measured the in vivo longitudinal data of these four parameters with tumor development and the corresponding presence and absence of tumor macrophage HIF-1α or HIF-2α in a mouse model of breast cancer. In the current paper, we present a mathematical model-based system of (ordinary and partial) differential equations to monitor tumor growth and susceptibility to standard chemotherapy with oxygen level, pH, and intracellular GSH concentration. We first show that our model simulations agree with the corresponding experiments, and then we use our model to suggest treatments of tumors by altering these four parameters in tumor microenvironment. For example, the model qualitatively predicts that GSH depletion can raise the level of reactive oxygen species (ROS) above a toxic threshold and result in inhibition of tumor growth. [ABSTRACT FROM AUTHOR]

Macrophages can account for up to 50% of tumour mass and secrete many angiogenic factors. Furthermore, tumour hypoxia is thought to play a major role in the activation of macrophages and the regulation of angiogenesis. In this paper, we demonstrate a strong correlation between hypoxia and the recruitment of immune cells binding to IgG in 8 experimental tumours. We provide evidence that IgG binding immune cells in 3 tumour lines are predominately composed of macrophages. Reduced oxygenation may act as a stimulus for recruitment of immune cells to the tumour mass, and the detection of either IgG-positive host cells or macrophages may offer an alternative method for monitoring tumour hypoxia. [ABSTRACT FROM AUTHOR]

Simple Summary: The recent success of immunotherapy treatments against cancer relies on helping our own body's defenses in the fight against tumours, namely reinvigorating the cancer killing action of T cells. Unfortunately, in a large proportion of patients these therapies are ineffective, in part due to the presence of other immune cells, macrophages, which are mis-educated by the cancer cells into promoting tumour growth. Here we start from an existing model of macrophage polarization and extend it to the specific conditions encountered inside a tumour by adding signals, receptors, transcription factors and cytokines that are known to be the key components in establishing the cancer cell-macrophage interaction. Then we use a mathematical Boolean model applied to a gene regulatory network of this biological process to simulate its temporal behaviour and explore scenarios that have not been experimentally tested so far. Additionally, the KO and overexpression simulations successfully reproduce the known experimental results while predicting the potential role of regulators (such as STAT1 and EGF) in preventing the formation of pro-tumoural macrophages, which can be tested experimentally. The tumour microenvironment is the surrounding of a tumour, including blood vessels, fibroblasts, signaling molecules, the extracellular matrix and immune cells, especially neutrophils and monocyte-derived macrophages. In a tumour setting, macrophages encompass a spectrum between a tumour-suppressive (M1) or tumour-promoting (M2) state. The biology of macrophages found in tumours (Tumour Associated Macrophages) remains unclear, but understanding their impact on tumour progression is highly important. In this paper, we perform a comprehensive analysis of a macrophage polarization network, following two lines of enquiry: (i) we reconstruct the macrophage polarization network based on literature, extending it to include important stimuli in a tumour setting, and (ii) we build a dynamical model able to reproduce macrophage polarization in the presence of different stimuli, including the contact with cancer cells. Our simulations recapitulate the documented macrophage phenotypes and their dependencies on specific receptors and transcription factors, while also unravelling the formation of a special type of tumour associated macrophages in an in vitro model of chronic lymphocytic leukaemia. This model constitutes the first step towards elucidating the cross-talk between immune and cancer cells inside tumours, with the ultimate goal of identifying new therapeutic targets that could control the formation of tumour associated macrophages in patients. [ABSTRACT FROM AUTHOR]

Presents abstracts of papers published in the November 2002 issue of the "Journal of Biomedical Science." "Physiological Indicators of Sepsis"; "Protective Tumor Immunity from Repeated DNA Vaccination"; "Macrophage-Tropic HIV-1 Infects Alveolar and Blood Monocyte-Derived Macrophages."