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  1. Article: Critical role of CD206+ macrophages in organizing anti-tumor immunity.

    Ray, Arja / Hu, Kenneth H / Kersten, Kelly / Kuhn, Nicholas F / Samad, Bushra / Combes, Alexis J / Krummel, Matthew F

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Tumor-associated macrophages (TAMs) are frequently and simplistically categorized as immunosuppressive, and one molecule prominently used to highlight their so-called 'M2' state is the surface protein CD206. However, direct evidence of the impact of ... ...

    Abstract Tumor-associated macrophages (TAMs) are frequently and simplistically categorized as immunosuppressive, and one molecule prominently used to highlight their so-called 'M2' state is the surface protein CD206. However, direct evidence of the impact of macrophages remains impaired by the lack of sufficiently penetrant and specific tools to manipulate them in vivo. We thus made a novel conditional CD206 knock-in mouse to specifically visualize and/or deplete these TAMs. Early depletion of CD206+ macrophages and monocytes (here, 'MonoMacs') strikingly led to an indirect loss of a key anti-tumor network of NK cells, conventional type I dendritic cells (cDC1) and CD8 T cells. Among myeloid cells, we found that the CD206+ TAMs are the primary producers of CXCL9, the well-established chemoattractant for CXCR3-expressing NK and CD8 T cells. In contrast, a population of stress-responsive TAMs ("Hypoxic" or
    Language English
    Publishing date 2023-11-02
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.10.31.560822
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Uptake of tumor-derived microparticles induces metabolic reprogramming of macrophages in the early metastatic lung.

    Kersten, Kelly / You, Ran / Liang, Sophia / Tharp, Kevin M / Pollack, Joshua / Weaver, Valerie M / Krummel, Matthew F / Headley, Mark B

    Cell reports

    2023  Volume 42, Issue 6, Page(s) 112582

    Abstract: Pre-metastatic niche formation is a critical step during the metastatic spread of cancer. One way by which primary tumors prime host cells at future metastatic sites is through the shedding of tumor-derived microparticles as a consequence of vascular ... ...

    Abstract Pre-metastatic niche formation is a critical step during the metastatic spread of cancer. One way by which primary tumors prime host cells at future metastatic sites is through the shedding of tumor-derived microparticles as a consequence of vascular sheer flow. However, it remains unclear how the uptake of such particles by resident immune cells affects their phenotype and function. Here, we show that ingestion of tumor-derived microparticles by macrophages induces a rapid metabolic and phenotypic switch that is characterized by enhanced mitochondrial mass and function, increased oxidative phosphorylation, and upregulation of adhesion molecules, resulting in reduced motility in the early metastatic lung. This reprogramming event is dependent on signaling through the mTORC1, but not the mTORC2, pathway and is induced by uptake of tumor-derived microparticles. Together, these data support a mechanism by which uptake of tumor-derived microparticles induces reprogramming of macrophages to shape their fate and function in the early metastatic lung.
    MeSH term(s) Humans ; Macrophages/pathology ; Lung/pathology ; Neoplasms/pathology ; Signal Transduction ; Biological Transport ; Lung Neoplasms/pathology
    Language English
    Publishing date 2023-05-31
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2649101-1
    ISSN 2211-1247 ; 2211-1247
    ISSN (online) 2211-1247
    ISSN 2211-1247
    DOI 10.1016/j.celrep.2023.112582
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: Tumor cell heterogeneity drives spatial organization of the intratumoral immune response in squamous cell skin carcinoma.

    Tanaka, Miho / Lum, Lotus / Hu, Kenneth / Ledezma-Soto, Cecilia / Samad, Bushra / Superville, Daphne / Ng, Kenneth / Adams, Zoe / Kersten, Kelly / Fong, Lawrence / Combes, Alexis J / Krummel, Matthew / Reeves, Melissa

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Intratumoral heterogeneity (ITH)-defined as genetic and cellular diversity within a tumor-is linked to failure of immunotherapy and an inferior anti-tumor immune response. The underlying mechanism of this association is unknown. To address this question, ...

    Abstract Intratumoral heterogeneity (ITH)-defined as genetic and cellular diversity within a tumor-is linked to failure of immunotherapy and an inferior anti-tumor immune response. The underlying mechanism of this association is unknown. To address this question, we modeled heterogeneous tumors comprised of a pro-inflammatory ("hot") and an immunosuppressive ("cold") tumor population, labeled with YFP and RFP tags respectively to enable precise spatial tracking. The resulting mixed-population tumors exhibited distinct regions comprised of YFP
    Language English
    Publishing date 2023-06-21
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.04.25.538140
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Neoadjuvant immune checkpoint blockade triggers persistent and systemic T

    Blomberg, Olga S / Kos, Kevin / Spagnuolo, Lorenzo / Isaeva, Olga I / Garner, Hannah / Wellenstein, Max D / Bakker, Noor / Duits, Danique E M / Kersten, Kelly / Klarenbeek, Sjoerd / Hau, Cheei-Sing / Kaldenbach, Daphne / Raeven, Elisabeth A M / Vrijland, Kim / Kok, Marleen / de Visser, Karin E

    Oncoimmunology

    2023  Volume 12, Issue 1, Page(s) 2201147

    Abstract: The clinical successes of immune checkpoint blockade (ICB) in advanced cancer patients have recently spurred the clinical implementation of ICB in the neoadjuvant and perioperative setting. However, how neoadjuvant ICB therapy affects the systemic immune ...

    Abstract The clinical successes of immune checkpoint blockade (ICB) in advanced cancer patients have recently spurred the clinical implementation of ICB in the neoadjuvant and perioperative setting. However, how neoadjuvant ICB therapy affects the systemic immune landscape and metastatic spread remains to be established. Tumors promote both local and systemic expansion of regulatory T cells (T
    MeSH term(s) Humans ; Breast Neoplasms/immunology ; Breast Neoplasms/therapy ; Lymphocyte Activation ; T-Lymphocytes, Regulatory/immunology ; Neoadjuvant Therapy ; Immune Checkpoint Inhibitors/therapeutic use ; Killer Cells, Natural/immunology ; Myeloid Cells/immunology ; Neoplasm Metastasis ; Animals ; Mice ; CD8-Positive T-Lymphocytes/immunology
    Chemical Substances Immune Checkpoint Inhibitors
    Language English
    Publishing date 2023-04-13
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2645309-5
    ISSN 2162-402X ; 2162-402X
    ISSN (online) 2162-402X
    ISSN 2162-402X
    DOI 10.1080/2162402X.2023.2201147
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: Exploiting the Immunomodulatory Properties of Chemotherapeutic Drugs to Improve the Success of Cancer Immunotherapy.

    Kersten, Kelly / Salvagno, Camilla / de Visser, Karin E

    Frontiers in immunology

    2015  Volume 6, Page(s) 516

    Abstract: Cancer immunotherapy is gaining momentum in the clinic. The current challenge is to understand why a proportion of cancer patients do not respond to cancer immunotherapy, and how this can be translated into the rational design of combinatorial cancer ... ...

    Abstract Cancer immunotherapy is gaining momentum in the clinic. The current challenge is to understand why a proportion of cancer patients do not respond to cancer immunotherapy, and how this can be translated into the rational design of combinatorial cancer immunotherapy strategies aimed at maximizing success of immunotherapy. Here, we discuss how tumors orchestrate an immunosuppressive microenvironment, which contributes to their escape from immune attack. Relieving the immunosuppressive networks in cancer patients is an attractive strategy to extend the clinical success of cancer immunotherapy. Since the clinical availability of drugs specifically targeting immunosuppressive cells or mediators is still limited, an alternative strategy is to use conventional chemotherapy drugs with immunomodulatory properties to improve cancer immunotherapy. We summarize the preclinical and clinical studies that illustrate how the anti-tumor T cell response can be enhanced by chemotherapy-induced relief of immunosuppressive networks. Treatment strategies aimed at combining chemotherapy-induced relief of immunosuppression and T cell-boosting checkpoint inhibitors provide an attractive and clinically feasible approach to overcome intrinsic and acquired resistance to cancer immunotherapy, and to extend the clinical success of cancer immunotherapy.
    Language English
    Publishing date 2015-10-07
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2606827-8
    ISSN 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2015.00516
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Spatiotemporal co-dependency between macrophages and exhausted CD8

    Kersten, Kelly / Hu, Kenneth H / Combes, Alexis J / Samad, Bushra / Harwin, Tory / Ray, Arja / Rao, Arjun Arkal / Cai, En / Marchuk, Kyle / Artichoker, Jordan / Courau, Tristan / Shi, Quanming / Belk, Julia / Satpathy, Ansuman T / Krummel, Matthew F

    Cancer cell

    2022  Volume 40, Issue 6, Page(s) 624–638.e9

    Abstract: T cell exhaustion is a major impediment to antitumor immunity. However, it remains elusive how other immune cells in the tumor microenvironment (TME) contribute to this dysfunctional state. Here, we show that the biology of tumor-associated macrophages ( ... ...

    Abstract T cell exhaustion is a major impediment to antitumor immunity. However, it remains elusive how other immune cells in the tumor microenvironment (TME) contribute to this dysfunctional state. Here, we show that the biology of tumor-associated macrophages (TAMs) and exhausted T cells (T
    MeSH term(s) CD8-Positive T-Lymphocytes ; Cell Differentiation ; Humans ; Macrophages ; Neoplasms/genetics ; Tumor Microenvironment
    Language English
    Publishing date 2022-05-26
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2078448-X
    ISSN 1878-3686 ; 1535-6108
    ISSN (online) 1878-3686
    ISSN 1535-6108
    DOI 10.1016/j.ccell.2022.05.004
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Genetically engineered mouse models in oncology research and cancer medicine.

    Kersten, Kelly / de Visser, Karin E / van Miltenburg, Martine H / Jonkers, Jos

    EMBO molecular medicine

    2016  Volume 9, Issue 2, Page(s) 137–153

    Abstract: Genetically engineered mouse models (GEMMs) have contributed significantly to the field of cancer research. In contrast to cancer cell inoculation models, GEMMs develop de novo tumors in a natural immune-proficient microenvironment. Tumors arising in ... ...

    Abstract Genetically engineered mouse models (GEMMs) have contributed significantly to the field of cancer research. In contrast to cancer cell inoculation models, GEMMs develop de novo tumors in a natural immune-proficient microenvironment. Tumors arising in advanced GEMMs closely mimic the histopathological and molecular features of their human counterparts, display genetic heterogeneity, and are able to spontaneously progress toward metastatic disease. As such, GEMMs are generally superior to cancer cell inoculation models, which show no or limited heterogeneity and are often metastatic from the start. Given that GEMMs capture both tumor cell-intrinsic and cell-extrinsic factors that drive de novo tumor initiation and progression toward metastatic disease, these models are indispensable for preclinical research. GEMMs have successfully been used to validate candidate cancer genes and drug targets, assess therapy efficacy, dissect the impact of the tumor microenvironment, and evaluate mechanisms of drug resistance. In vivo validation of candidate cancer genes and therapeutic targets is further accelerated by recent advances in genetic engineering that enable fast-track generation and fine-tuning of GEMMs to more closely resemble human patients. In addition, aligning preclinical tumor intervention studies in advanced GEMMs with clinical studies in patients is expected to accelerate the development of novel therapeutic strategies and their translation into the clinic.
    MeSH term(s) Animals ; Animals, Genetically Modified ; Disease Models, Animal ; Humans ; Medical Oncology/methods ; Mice ; Neoplasms/pathology ; Neoplasms/therapy
    Language English
    Publishing date 2016-12-27
    Publishing country England
    Document type Journal Article ; Review ; Research Support, Non-U.S. Gov't
    ZDB-ID 2467145-9
    ISSN 1757-4684 ; 1757-4676
    ISSN (online) 1757-4684
    ISSN 1757-4676
    DOI 10.15252/emmm.201606857
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: ZipSeq: barcoding for real-time mapping of single cell transcriptomes.

    Hu, Kenneth H / Eichorst, John P / McGinnis, Chris S / Patterson, David M / Chow, Eric D / Kersten, Kelly / Jameson, Stephen C / Gartner, Zev J / Rao, Arjun A / Krummel, Matthew F

    Nature methods

    2020  Volume 17, Issue 8, Page(s) 833–843

    Abstract: Spatial transcriptomics seeks to integrate single cell transcriptomic data within the three-dimensional space of multicellular biology. Current methods to correlate a cell's position with its transcriptome in living tissues have various limitations. We ... ...

    Abstract Spatial transcriptomics seeks to integrate single cell transcriptomic data within the three-dimensional space of multicellular biology. Current methods to correlate a cell's position with its transcriptome in living tissues have various limitations. We developed an approach, called 'ZipSeq', that uses patterned illumination and photocaged oligonucleotides to serially print barcodes ('zipcodes') onto live cells in intact tissues, in real time and with an on-the-fly selection of patterns. Using ZipSeq, we mapped gene expression in three settings: in vitro wound healing, live lymph node sections and a live tumor microenvironment. In all cases, we discovered new gene expression patterns associated with histological structures. In the tumor microenvironment, this demonstrated a trajectory of myeloid and T cell differentiation from the periphery inward. A combinatorial variation of ZipSeq efficiently scales in the number of regions defined, providing a pathway for complete mapping of live tissues, subsequent to real-time imaging or perturbation.
    MeSH term(s) Animals ; Computational Biology ; DNA Barcoding, Taxonomic/methods ; Gene Expression Regulation ; Lymph Nodes ; Mice ; NIH 3T3 Cells ; Single-Cell Analysis/methods ; T-Lymphocytes ; Transcriptome/genetics ; Tumor Microenvironment
    Language English
    Publishing date 2020-07-06
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2169522-2
    ISSN 1548-7105 ; 1548-7091
    ISSN (online) 1548-7105
    ISSN 1548-7091
    DOI 10.1038/s41592-020-0880-2
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Lessons for the Next Generation of Scientists from the Second Annual Arthur and Sandra Irving Cancer Immunology Symposium.

    Alvarez-Breckenridge, Christopher / Anderson, Kristin G / Correia, Ana Luisa / Demehri, Shadmehr / Dinh, Huy Q / Dixon, Karen Olivia / Dunn, Gavin P / Evgin, Laura / Goc, Jeremy / Good, Zinaida / Hacohen, Nir / Han, Patrick / Hanč, Pavel / Hickey, John / Kersten, Kelly / Liu, Beiyun C / Buque, Aitziber / Miao, Yuxuan 'Phoenix' / Milner, J Justin /
    Pritykin, Yuri / Pucci, Ferdinando / Scharping, Nicole E / Sudmeier, Lisa / Wang, Yufei / Wieland, Andreas / Williams, Michelle M

    Cancer immunology research

    2023  Volume 11, Issue 12, Page(s) 1571–1577

    Abstract: The Arthur and Sandra Irving Cancer Immunology Symposium has been created as a platform for established cancer immunologists to mentor trainees and young investigators as they launch their research career in the field. By sharing their different paths to ...

    Abstract The Arthur and Sandra Irving Cancer Immunology Symposium has been created as a platform for established cancer immunologists to mentor trainees and young investigators as they launch their research career in the field. By sharing their different paths to success, the senior faculty mentors provide an invaluable resource to support the development of the next generation of leaders in the cancer immunology community. This Commentary describes some of the key topics that were discussed during the 2022 symposium: scientific and career trajectory, leadership, mentoring, collaborations, and publishing. For each of these topics, established investigators discussed the elements that facilitate success in these areas as well as mistakes that can hinder progress. Herein, we outline the critical points raised in these discussions for establishing a successful independent research career. These points are highly relevant for the broader scientific community.
    MeSH term(s) Humans ; Mentoring ; Mentors ; Physicians ; Research Personnel ; Neoplasms/therapy
    Language English
    Publishing date 2023-10-31
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2732489-8
    ISSN 2326-6074 ; 2326-6066
    ISSN (online) 2326-6074
    ISSN 2326-6066
    DOI 10.1158/2326-6066.CIR-23-0522
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article: Response of metastatic mouse invasive lobular carcinoma to mTOR inhibition is partly mediated by the adaptive immune system.

    Klarenbeek, Sjoerd / Doornebal, Chris W / Kas, Sjors M / Bonzanni, Nicola / Bhin, Jinhyuk / Braumuller, Tanya M / van der Heijden, Ingrid / Opdam, Mark / Schouten, Philip C / Kersten, Kelly / de Bruijn, Roebi / Zingg, Daniel / Yemelyanenko, Julia / Wessels, Lodewyk F A / de Visser, Karin E / Jonkers, Jos

    Oncoimmunology

    2020  Volume 9, Issue 1, Page(s) 1724049

    Abstract: Effective treatment of invasive lobular carcinoma (ILC) of the breast is hampered by late detection, invasive growth, distant metastasis, and poor response to chemotherapy. Phosphoinositide 3-kinase (PI3K) signaling, one of the major druggable oncogenic ... ...

    Abstract Effective treatment of invasive lobular carcinoma (ILC) of the breast is hampered by late detection, invasive growth, distant metastasis, and poor response to chemotherapy. Phosphoinositide 3-kinase (PI3K) signaling, one of the major druggable oncogenic signaling networks, is frequently activated in ILC. We investigated treatment response and resistance to AZD8055, an inhibitor of mammalian target of rapamycin (mTOR), in the
    MeSH term(s) Animals ; Breast Neoplasms/drug therapy ; Carcinoma, Lobular/drug therapy ; Female ; Humans ; Immune System ; Mice ; Phosphatidylinositol 3-Kinases ; TOR Serine-Threonine Kinases/genetics
    Chemical Substances MTOR protein, human (EC 2.7.1.1) ; TOR Serine-Threonine Kinases (EC 2.7.1.1)
    Language English
    Publishing date 2020-02-12
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2645309-5
    ISSN 2162-402X ; 2162-4011
    ISSN (online) 2162-402X
    ISSN 2162-4011
    DOI 10.1080/2162402X.2020.1724049
    Database MEDical Literature Analysis and Retrieval System OnLINE

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