Natural killer T cell activation overcomes immunosuppression to enhance clearance of postsurgical breast cancer metastasis in mice

Gebremeskel, Simon; Clattenburg, Daniel R.; Slauenwhite, Drew; Lobert, Lynnea; Johnston, Brent

doi:10.1080/2162402x.2014.995562

Cited by 53 publications

(77 citation statements)

References 62 publications

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“…However, in renal cell carcinoma patients, the expression of CD1b is associated with high relapse and poor prognosis (Chong et al 2015). The administration of retinoic acid and αGalCer (iNKT agonist) alone or the transfusion of αGalCer-loaded DCs reduces the tumor size and the number of metastatic foci in a mouse model of breast cancer by enhancing CD8 + T-cell cytotoxicity (Chen and Ross 2012;Gebremeskel et al 2015). A phase I-II study on patients with advanced lung cancer arrived at similar conclusions (Motohashi et al 2009).…”

Section: Invariant Nk T (Inkt) Cellsmentioning

confidence: 93%

Roles of the immune system in cancer: from tumor initiation to metastatic progression

2018

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The presence of inflammatory immune cells in human tumors raises a fundamental question in oncology: How do cancer cells avoid the destruction by immune attack? In principle, tumor development can be controlled by cytotoxic innate and adaptive immune cells; however, as the tumor develops from neoplastic tissue to clinically detectable tumors, cancer cells evolve different mechanisms that mimic peripheral immune tolerance in order to avoid tumoricidal attack. Here, we provide an update of recent accomplishments, unifying concepts, and future challenges to study tumor-associated immune cells, with an emphasis on metastatic carcinomas.

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Section: Invariant Nk T (Inkt) Cellsmentioning

confidence: 93%

Roles of the immune system in cancer: from tumor initiation to metastatic progression

2018

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“…NKT cells regulate innate and adaptive immune responses and contribute to tumor immu-nosurveillance (2), likely through detection of stress-induced glycolipids, tumor-associated glycolipid antigens, and/or inflammatory cytokines. Therapeutic NKT-cell activation provides protection from tumor development and progression in animal models (3)(4)(5)(6)(7)(8)(9), and induces lasting antitumor immunity (5,7). In clinical studies, NKT-cell activation therapies stabilized disease in head and neck cancer patients (10,11) and prolonged median survival time in lung cancer patients (12).…”

Section: Introductionmentioning

confidence: 99%

Natural Killer T-cell Immunotherapy in Combination with Chemotherapy-Induced Immunogenic Cell Death Targets Metastatic Breast Cancer

Gebremeskel

Lobert

Tanner

et al. 2017

Cancer Immunology Research

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Natural killer T (NKT) cells are glycolipid-reactive lymphocytes that promote cancer control. In previous studies, NKT-cell activation improved survival and antitumor immunity in a postsurgical mouse model of metastatic breast cancer. Herein, we investigated whether NKT-cell activation could be combined with chemotherapeutic agents to augment therapeutic outcomes. Gemcitabine and cyclophosphamide analogues enhanced the potential immunogenicity of 4T1 mammary carcinoma cells by increasing the expression of antigen-presenting molecules (MHC-I, MHC-II, and CD1d) and promoting exposure or release of immunogenic cell death markers (calreticulin, HMGB1, and ATP). In 4T1 primary tumor and postsurgical metastasis models, BALB/c mice were treated with cyclophosphamide or gemcitabine. NKT cells were then activated by transfer of dendritic cells loaded with the glycolipid antigen α-galactosylceramide (α-GalCer). Chemotherapeutic treatments did not impact NKT-cell activation but enhanced recruitment into primary tumors. Cyclophosphamide, gemcitabine, or α-GalCer-loaded dendritic cell monotherapies decreased tumor growth in the primary tumor model and reduced metastatic burden and prolonged survival in the metastasis model. Combining chemotherapeutics with NKT-cell activation therapy significantly enhanced survival, with surviving mice exhibiting attenuated tumor growth following a second tumor challenge. The frequency of myeloid-derived suppressor cells was reduced by gemcitabine, cyclophosphamide, or α-GalCer-loaded dendritic cell treatments; cyclophosphamide also reduced the frequency of regulatory T cells. Individual treatments increased immune cell activation, cytokine polarization, and cytotoxic responses, although these readouts were not enhanced further by combining therapies. These findings demonstrate that NKT-cell activation therapy can be combined with gemcitabine or cyclophosphamide to target tumor burden and enhance protection against tumor recurrence. .

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“…However, once a postoperative recurrence occurs, it is directly related to death. In the relapse model after resection of the primary tumor in a triplenegative breast tumor, treatment with α-GalCer-loaded DCs limited tumor metastasis, prolonged survival, and provided curative outcomes (50). We elucidated that the frequency of MDSCs of the peripheral blood can be a recurrence marker in a B16 melanoma model (51).…”

Section: Modulation Of Immunosuppressive Tumor Microenvironmentmentioning

confidence: 99%

Application of iNKT Cell-targeted Active Immunotherapy in Cancer Treatment

et al. 2018

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In tumor immunity, invariant natural killer T (iNKT) cells play a pivotal role as a link between the innate and adaptive immune systems. With a precisely regulated activation mechanism, iNKT cells have the ability to respond quickly to antigenic stimulation and rapidly produce cytokines and chemokines, and subsequently an effective antitumor immune response. The development of iNKT cell-targeted active immunotherapy enables, not only an antitumor immune response through innate and acquired immunity, but also the conversion of an immunosuppressive into an immunogenic microenvironment. This review is focused on the activation mechanism and the role of iNKT cells after therapeutic active immunization. The therapeutic strategy targeting iNKT cells is expected to be applied to clinical practice in combination with surgery and chemotherapy.

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Natural killer T cell activation overcomes immunosuppression to enhance clearance of postsurgical breast cancer metastasis in mice

Cited by 53 publications

References 62 publications

Roles of the immune system in cancer: from tumor initiation to metastatic progression

Roles of the immune system in cancer: from tumor initiation to metastatic progression

Natural Killer T-cell Immunotherapy in Combination with Chemotherapy-Induced Immunogenic Cell Death Targets Metastatic Breast Cancer

Application of iNKT Cell-targeted Active Immunotherapy in Cancer Treatment

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