scholarly journals Multiscale Agent-Based and Hybrid Modeling of the Tumor Immune Microenvironment

Processes ◽  
2019 ◽  
Vol 7 (1) ◽  
pp. 37 ◽  
Author(s):  
Kerri-Ann Norton ◽  
Chang Gong ◽  
Samira Jamalian ◽  
Aleksander Popel
Keyword(s):  
Immune Response ◽  
Tumor Heterogeneity ◽  
Computational Models ◽  
Digital Pathology ◽  
Hybrid Modeling ◽  
Immune Microenvironment ◽  
Agent Based ◽  
Tumor Immune Microenvironment ◽  
Cancer Tumor

Multiscale systems biology and systems pharmacology are powerful methodologies that are playing increasingly important roles in understanding the fundamental mechanisms of biological phenomena and in clinical applications. In this review, we summarize the state of the art in the applications of agent-based models (ABM) and hybrid modeling to the tumor immune microenvironment and cancer immune response, including immunotherapy. Heterogeneity is a hallmark of cancer; tumor heterogeneity at the molecular, cellular, and tissue scales is a major determinant of metastasis, drug resistance, and low response rate to molecular targeted therapies and immunotherapies. Agent-based modeling is an effective methodology to obtain and understand quantitative characteristics of these processes and to propose clinical solutions aimed at overcoming the current obstacles in cancer treatment. We review models focusing on intra-tumor heterogeneity, particularly on interactions between cancer cells and stromal cells, including immune cells, the role of tumor-associated vasculature in the immune response, immune-related tumor mechanobiology, and cancer immunotherapy. We discuss the role of digital pathology in parameterizing and validating spatial computational models and potential applications to therapeutics.

scholarly journals Characterization of the Tumor Immune Microenvironment in Lung Squamous Cell Carcinoma Using Imaging Mass Cytometry

2021 ◽  
Vol 11 ◽  
Author(s):  
Ran Li ◽  
Ying Lin ◽  
Yu Wang ◽  
Shaoyuan Wang ◽  
Yang Yang ◽  
...  
Keyword(s):  
Immune Response ◽  
Squamous Cell Carcinoma ◽  
T Cells ◽  
Tumor Microenvironment ◽  
Lung Squamous Cell Carcinoma ◽  
Mass Cytometry ◽  
Immune Microenvironment ◽  
Tumor Immune Microenvironment ◽  
Tumor Region ◽  
Proinflammatory Role

BackgroundLung squamous cell carcinoma (LUSC) is a major subtype of non-small cell lung cancer. The tumor immune microenvironment (TIME) affects the anti-tumor immune response and the patient’s prognosis, although the TIME in LUSC patients is incompletely understood.MethodsWe retrospectively collected surgical specimens from patients with previously untreated primary LUSC. Histopathological examination was used to identify tumor regions and adjacent regions, and imaging mass cytometry was used to characterize the immune cells in those regions. The results were compared between regions and between patients.ResultsWe identified heterogeneity in the TIME on comparing different patients with LUSC, although the tumor region and adjacent region both exhibited an immune response to the tumor. The TIME typically included a large number of infiltrating and activated T-cells, especially CD8+ T-cells, which closely interacted with the tumor cells in the tumor region. There was limited infiltration of B-cells, NK cells, and NKT cells, while the major immune suppressor cells were CD33+ myeloid-derived cells. We also identified a novel population of CD3−CD4+ cells with high expression of Foxp3 and TNFα, which might modulate the tumor microenvironment and play a proinflammatory role in the TIME.ConclusionsThe TIME of LUSC appears to be immunogenic and heterogenous, with predominant infiltration of activated CD8+ T-cells. The interactions between the tumor cells and T-cells facilitate the anti-tumor activity. A novel subpopulation of CD3−CD4+ cells with high TNFα and Foxp3 expression may modulate the tumor microenvironment and play a proinflammatory role.

scholarly journals Single-cell tumor-immune microenvironment of BRCA1/2 mutated high-grade serous ovarian cancer

2021 ◽  
Author(s):  
Inga-Maria Launonen ◽  
Nuppu Lyytikäinen ◽  
Julia Casado ◽  
Ella Anttila ◽  
Angéla Szabó ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Single Cell ◽  
Single Cells ◽  
High Grade ◽  
Prognostic Role ◽  
Immune Microenvironment ◽  
Proteomic Data ◽  
Tumor Immune Microenvironment ◽  
Cellular Phenotypes

Abstract The majority of high-grade serous ovarian cancers (HGSCs) are deficient in homologous recombination (HR) DNA repair, most commonly due to mutations or hypermethylation of the BRCA1/2 genes. We aimed to discover how BRCA1/2 mutations shape the cellular phenotypes and spatial interactions of the tumor microenvironment. Using a highly multiplex immunofluorescence and image analysis we generated spatial proteomic data for 21 markers in 124,623 single cells from 112 tumor cores originating from 31 tumors with BRCA1/2 mutation (BRCA1/2mut), and from 13 tumors without alterations in HR genes (HRwt). We identified a phenotypically distinct tumor microenvironment in the BRCA1/2mut tumors with evidence of increased immunosurveillance. Importantly, we found an opposing prognostic role of a proliferative tumor-cell phenotypic subpopulation in the HR-genotypes, which associated with enhanced spatial tumor-immune interactions by the CD8+ and CD4+T-cells in BRCA1/2mut tumors. The single-cell spatial landscapes indicate distinct patterns of spatial immunosurveillance with the premise to improve immunotherapeutic strategies and patient stratification in HGSC.

scholarly journals Matter of TIME: the tumor-immune microenvironment of mesothelioma and implications for checkpoint blockade efficacy

2021 ◽  
Vol 9 (9) ◽  
pp. e003032
Author(s):  
James Harber ◽  
Tamihiro Kamata ◽  
Catrin Pritchard ◽  
Dean Fennell
Keyword(s):  
Treatment Options ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Phase Iii ◽  
Immune Microenvironment ◽  
Incurable Cancer ◽  
Phase Iii Clinical Trials ◽  
Dismal Prognosis ◽  
Tumor Immune Microenvironment ◽  
Cancer Tumor

Malignant pleural mesothelioma (MPM) is an incurable cancer with a dismal prognosis and few effective treatment options. Nonetheless, recent positive phase III trial results for immune checkpoint blockade (ICB) in MPM herald a new dawn in the fight to advance effective treatments for this cancer. Tumor mutation burden (TMB) has been widely reported to predict ICB in other cancers, but MPM is considered a low-TMB tumor. Similarly, tumor programmed death-ligand 1 (PD-L1) expression has not been proven predictive in phase III clinical trials in MPM. Consequently, the precise mechanisms that determine response to immunotherapy in this cancer remain unknown. The present review therefore aimed to synthesize our current understanding of the tumor immune microenvironment in MPM and reflects on how specific cellular features might impact immunotherapy responses or lead to resistance. This approach will inform stratified approaches to therapy and advance immunotherapy combinations in MPM to improve clinical outcomes further.

Abstract PO-041: Multiplexed ion beam imaging to describe tumor-immune microenvironment and tumor heterogeneity in neuroblastoma

2020 ◽  
Author(s):  
Marte B. Kammersgaard ◽  
Marc Bosse ◽  
Daniel Martinez ◽  
Kristopher R. Bosse ◽  
John M. Maris ◽  
...  
Keyword(s):  
Tumor Heterogeneity ◽  
Ion Beam ◽  
Immune Microenvironment ◽  
Tumor Immune Microenvironment

scholarly journals The Cutaneous Wound Innate Immunological Microenvironment

2020 ◽  
Vol 21 (22) ◽  
pp. 8748
Author(s):  
Stephen Kirchner ◽  
Vivian Lei ◽  
Amanda S. MacLeod
Keyword(s):  
Immune Response ◽  
Wound Repair ◽  
Immune Cell ◽  
Skin Barrier ◽  
Innate Immune ◽  
Immune Microenvironment ◽  
Cell Recruitment ◽  
Adaptive Processes ◽  
Immune Cell Recruitment

The skin represents the first line of defense and innate immune protection against pathogens. Skin normally provides a physical barrier to prevent infection by pathogens; however, wounds, microinjuries, and minor barrier impediments can present open avenues for invasion through the skin. Accordingly, wound repair and protection from invading pathogens are essential processes in successful skin barrier regeneration. To repair and protect wounds, skin promotes the development of a specific and complex immunological microenvironment within and surrounding the disrupted tissue. This immune microenvironment includes both innate and adaptive processes, including immune cell recruitment to the wound and secretion of extracellular factors that can act directly to promote wound closure and wound antimicrobial defense. Recent work has shown that this immune microenvironment also varies according to the specific context of the wound: the microbiome, neuroimmune signaling, environmental effects, and age play roles in altering the innate immune response to wounding. This review will focus on the role of these factors in shaping the cutaneous microenvironment and how this ultimately impacts the immune response to wounding.

scholarly journals Sexual dimorphism and the role of estrogen in the immune microenvironment of liver metastases

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Simon Milette ◽  
Masakazu Hashimoto ◽  
Stephanie Perrino ◽  
Shu Qi ◽  
Michely Chen ◽  
...  
Keyword(s):  
T Cells ◽  
Sexual Dimorphism ◽  
Liver Metastases ◽  
Suppressor Cells ◽  
Cytotoxic T Cell ◽  
Immune Microenvironment ◽  
Ovariectomized Mice ◽  
Cell Accumulation ◽  
Tumor Immune Microenvironment

AbstractLiver metastases (LM) remain a major cause of cancer-associated death and a clinical challenge. Here we explore a sexual dimorphism observed in the regulation of the tumor immune microenvironment (TIME) of LM, wherein the accumulation of myeloid-derived suppressor cells (MDSC) and regulatory T cells in colon and lung carcinoma LM is TNFR2-dependent in female, but not in male mice. In ovariectomized mice, a marked reduction is observed in colorectal, lung and pancreatic carcinoma LM that is reversible by estradiol reconstitution. This is associated with reduced liver MDSC accumulation, increased interferon-gamma (IFN-γ) and granzyme B production in CD8+ T cells and reduced TNFR2, IDO2, TDO and Serpin B9 expression levels. Treatment with tamoxifen increases liver cytotoxic T cell accumulation and reduces colon cancer LM. The results identify estrogen as a regulator of a pro-metastatic immune microenvironment in the liver and a potential target in the management of liver metastatic disease.

scholarly journals Tumor Immune Microenvironment and Its Related miRNAs in Tumor Progression

2021 ◽  
Vol 12 ◽  
Author(s):  
Yingying Xing ◽  
Guojing Ruan ◽  
Haiwei Ni ◽  
Hai Qin ◽  
Simiao Chen ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Progression ◽  
Tumor Cells ◽  
Immune Cells ◽  
Suppressor Cells ◽  
Immune Microenvironment ◽  
Non Coding Rna ◽  
Tumor Immune Microenvironment ◽  
Downstream Gene Expression

MiRNA is a type of small non-coding RNA, by regulating downstream gene expression that affects the progression of multiple diseases, especially cancer. MiRNA can participate in the biological processes of tumor, including proliferation, invasion and escape, and exhibit tumor enhancement or inhibition. The tumor immune microenvironment contains numerous immune cells. These cells include lymphocytes with tumor suppressor effects such as CD8+ T cells and natural killer cells, as well as some tumor-promoting cells with immunosuppressive functions, such as regulatory T cells and myeloid-derived suppressor cells. MiRNA can affect the tumor immune microenvironment by regulating the function of immune cells, which in turn modulates the progression of tumor cells. Investigating the role of miRNA in regulating the tumor immune microenvironment will help elucidate the specific mechanisms of interaction between immune cells and tumor cells, and may facilitate the use of miRNA as a predictor of immune disorders in tumor progression. This review summarizes the multifarious roles of miRNA in tumor progression through regulation of the tumor immune microenvironment, and provides guidance for the development of miRNA drugs to treat tumors and for the use of miRNA as an auxiliary means in tumor immunotherapy.

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