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      Modeling immune cell behavior across scales in cancer

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          Abstract

          Detailed, mechanistic models of immune cell behavior across multiple scales in the context of cancer provide clinically relevant insights needed to understand existing immunotherapies and develop more optimal treatment strategies. We highlight mechanistic models of immune cells and their ability to become activated and promote tumor cell killing. These models capture various aspects of immune cells: (a) single‐cell behavior by predicting the dynamics of intracellular signaling networks in individual immune cells, (b) multicellular interactions between tumor and immune cells, and (c) multiscale dynamics across space and different levels of biological organization. Computational modeling is shown to provide detailed quantitative insight into immune cell behavior and immunotherapeutic strategies. However, there are gaps in the literature, and we suggest areas where additional modeling efforts should be focused to more prominently impact our understanding of the complexities of the immune system in the context of cancer.

          This article is categorized under:

          • Biological Mechanisms > Cell Signaling

          • Models of Systems Properties and Processes > Mechanistic Models

          • Models of Systems Properties and Processes > Cellular Models

          Abstract

          A better understanding of immune cell response in tumors requires multiscale modeling of intracellular signaling, multicellular interactions, and spatial and whole‐body dynamics.

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          Most cited references56

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          Innate Immune Landscape in Early Lung Adenocarcinoma by Paired Single-Cell Analyses

          To guide the design of immunotherapy strategies for patients with early stage lung tumors, we developed a multiscale immune profiling strategy to map the immune landscape of early lung adenocarcinoma lesions to search for tumor-driven immune changes. Utilizing a barcoding method that allows a simultaneous single cell analysis of the tumor, non-involved lung and blood cells together with multiplex tissue imaging to assess spatial cell distribution, we provide a detailed immune cell atlas of early lung tumors. We show that stage I lung adenocarcinoma lesions already harbor significantly altered T cell and NK cell compartments. Moreover, we identified changes in tumor infiltrating myeloid cell (TIM) subsets that likely compromise anti-tumor T cell immunity. Paired single cell analyses thus offer valuable knowledge of tumor-driven immune changes, providing a powerful tool for the rational design of immune therapies. Comparing single tumor cells with adjacent normal tissue and blood from patients with lung adenocarcinoma charts early changes in tumor immunity and provides insights to guide immunotherapy design.
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            The head and neck cancer immune landscape and its immunotherapeutic implications.

            Recent clinical trials have demonstrated a clear survival advantage in advanced head and neck squamous cell carcinoma (HNSCC) patients treated with immune checkpoint blockade. These emerging results reveal that HNSCC is one of the most promising frontiers for immunotherapy research. However, further progress in head and neck immuno-oncology will require a detailed understanding of the immune infiltrative landscape found in these tumors. We leveraged transcriptome data from 280 tumors profiled by The Cancer Genome Atlas (TCGA) to comprehensively characterize the immune landscape of HNSCC in order to develop a rationale for immunotherapeutic strategies in HNSCC and guide clinical investigation. We find that both HPV(+) and HPV(-) HNSCC tumors are among the most highly immune-infiltrated cancer types. Strikingly, HNSCC had the highest median Treg/CD8(+) T cell ratio and the highest levels of CD56(dim) NK cell infiltration, in our pan-cancer analysis of the most immune-infiltrated tumors. CD8(+) T cell infiltration and CD56(dim) NK cell infiltration each correlated with superior survival in HNSCC. Tumors harboring genetic smoking signatures had lower immune infiltration and were associated with poorer survival, suggesting these patients may benefit from immune agonist therapy. These findings illuminate the immune landscape of HPV(+) and HPV(-) HNSCC. Additionally, this landscape provides a potentially novel rationale for investigation of agents targeting modulators of Tregs (e.g., CTLA-4, GITR, ICOS, IDO, and VEGFA) and NK cells (e.g., KIR, TIGIT, and 4-1BB) as adjuncts to anti-PD-1 in the treatment of advanced HNSCC.
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              Rae1 and H60 ligands of the NKG2D receptor stimulate tumour immunity.

              Natural killer (NK) cells attack many tumour cell lines, and are thought to have a critical role in anti-tumour immunity; however, the interaction between NK cells and tumour targets is poorly understood. The stimulatory lectin-like NKG2D receptor is expressed by NK cells, activated CD8+ T cells and by activated macrophages in mice. Several distinct cell-surface ligands that are related to class I major histocompatibility complex molecules have been identified, some of which are expressed at high levels by tumour cells but not by normal cells in adults. However, no direct evidence links the expression of these 'induced self' ligands with tumour cell rejection. Here we demonstrate that ectopic expression of the murine NKG2D ligands Rae1beta or H60 in several tumour cell lines results in potent rejection of the tumour cells by syngeneic mice. Rejection is mediated by NK cells and/or CD8+ T cells. The ligand-expressing tumour cells induce potent priming of cytotoxic T cells and sensitization of NK cells in vivo. Mice that are exposed to live or irradiated tumour cells expressing Rae1 or H60 are specifically immune to subsequent challenge with tumour cells that lack NKG2D ligands, suggesting application of the ligands in the design of tumour vaccines.
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                Author and article information

                Contributors
                sfinley@usc.edu
                Journal
                Wiley Interdiscip Rev Syst Biol Med
                Wiley Interdiscip Rev Syst Biol Med
                10.1002/(ISSN)1939-005X
                WSBM
                Wiley Interdisciplinary Reviews. Systems Biology and Medicine
                John Wiley & Sons, Inc. (Hoboken, USA )
                1939-5094
                1939-005X
                04 March 2020
                Jul-Aug 2020
                : 12
                : 4 ( doiID: 10.1002/wsbm.v12.4 )
                : e1484
                Affiliations
                [ 1 ] Department of Biomedical Engineering University of Southern California Los Angeles California USA
                [ 2 ] Department of Biomedical Engineering, Mork Family Department of Chemical Engineering and Materials Science, Department of Biological Sciences University of Southern California Los Angeles California USA
                Author notes
                [*] [* ] Correspondence

                Stacey D. Finley, Department of Biomedical Engineering, Mork Family Department of Chemical Engineering and Materials Science, Department of Biological Sciences, University of Southern California, Los Angeles, CA.

                Email: sfinley@ 123456usc.edu

                Sahak Z. Makaryan and Colin G. Cess contributed equally to this study.

                Author information
                https://orcid.org/0000-0001-6901-3692
                Article
                WSBM1484
                10.1002/wsbm.1484
                7317398
                32129950
                6dcf3e02-0d50-42cd-a6aa-2ea13b9a2ed7
                © 2020 The Authors. WIREs Systems Biology and Medicine published by Wiley Periodicals, Inc.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                : 09 October 2019
                : 07 January 2020
                : 04 February 2020
                Page count
                Figures: 3, Tables: 1, Pages: 16, Words: 11159
                Funding
                Funded by: American Cancer Society, Inc. , open-funder-registry 10.13039/100000048;
                Award ID: 130432‐RSG‐17‐133‐01‐CSM
                Funded by: Division of Chemical, Bioengineering, Environmental, and Transport Systems , open-funder-registry 10.13039/100000146;
                Award ID: 1552065
                Funded by: USC Graduate School
                Award ID: Provost's Fellowship
                Categories
                Cell Signaling
                Mechanistic Models
                Cellular Models
                Advanced Review
                Advanced Reviews
                Custom metadata
                2.0
                July/August 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.8.4 mode:remove_FC converted:26.06.2020

                Molecular medicine
                immune cell signaling,multiscale modeling,systems biology,tumor‐immune interactions

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