Inhaled IL-10 Suppresses Lung Tumorigenesis via Abrogation of Inflammatory Macrophage–Th17 Cell Axis

Li, Qingsheng; Anderson, Charles D.; Egilmez, Nejat K.

doi:10.4049/jimmunol.1800141

Cited by 29 publications

(19 citation statements)

References 39 publications

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“…25 The number of alveolar macrophages is associated with the degree of tumor progression, and M2 features of alveolar macrophages are increased during tumor progression. 25,26 Therefore, we examined whether changes in the absolute number or the phenotype of alveolar macrophages occur upon depletion of tumor-associated Tregs. Tregs ablation switched the activation status of BALF macrophages from an immunosuppressive M2-like major histocompatibility complex class II (MHC-II) low to a more inflammatory M1-like (MHC-II + ) state (Figure 7a).…”

Section: Tregs Ablation Resulted In Suppression Of M2 Type Of Macrophmentioning

confidence: 99%

Targeting ST2 expressing activated regulatory T cells in Kras-mutant lung cancer

et al. 2019

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Oncogenic KRAS-mutant lung cancers remain treatment refractory. A better understanding of the immune response of KRAS-mutant lung cancers is required to facilitate the development of potential therapeutic strategies. Regulatory T cells (Tregs) are a subset of immune cells that promote tumor progression through suppressing anti-tumor immune response. Here, we used Kras G12D lung cancer mice to examine the characteristics of tumor-infiltrating Tregs. In tumor-bearing animals, Tregs are increased during tumor progression. Of note, a majority of Tregs that localized in lung tumors of Krasmutant mice expressed ST2, a receptor for IL-33, which are different from Tregs in secondary lymphoid organs. To investigate the function of local Tregs influencing immune response in primary lung tumor development, we used anti-ST2 antibody to deplete Tregs in lung tumors of Kras-mutant mice. Treatment of Kras-mutant mice with anti-ST2 antibody resulted in depletion of activated Tregs in lung tumor while leaving Tregs in secondary lymphoid organs intact. Also, localized Tregs depletion led to a significant reduction in lung tumor burden. Immune response after Tregs depletion in tumors showed restoration of NK cell activity and enhanced Th1 activity, with increased CD8 cytotoxic T cell response. In addition, we found that the M2 macrophage signature in lung tumors was suppressed upon Tregs depletion, accompanied by upregulation of surface expression of MHC-II molecules and reduced expression of Arg1, Mmp12, Cxcl2, and Chi3l3. These data suggest that therapeutic strategies targeting activated Tregs in lung cancer have the potential to restrain tumor progression by enhancing anti-tumor immunity.

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Section: Tregs Ablation Resulted In Suppression Of M2 Type Of Macrophmentioning

confidence: 99%

Targeting ST2 expressing activated regulatory T cells in Kras-mutant lung cancer

et al. 2019

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“…Antibiotic treatment was ceased followed by fecal microbiota transplants (FMT) on 3 consecutive days. Fecal pellets were collected from each mouse prior to adenoviral-cre (Viral Vector Core Facility, University of Iowa) infection, and lung histological slides were done as described by Li et al [32]. Briefly, adenoviral infection was performed intranasally in anesthetized mouse with isoflurane at 2.5 × 10 7 PFUs per mouse in two 30-μL installations.…”

Section: Kras-driven Lung Adenocarcinomamentioning

confidence: 99%

Temporospatial shifts within commercial laboratory mouse gut microbiota impact experimental reproducibility

et al. 2020

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Background Experimental reproducibility in mouse models is impacted by both genetics and environment. The generation of reproducible data is critical for the biomedical enterprise and has become a major concern for the scientific community and funding agencies alike. Among the factors that impact reproducibility in experimental mouse models is the variable composition of the microbiota in mice supplied by different commercial vendors. Less attention has been paid to how the microbiota of mice supplied by a particular vendor might change over time. Results In the course of conducting a series of experiments in a mouse model of malaria, we observed a profound and lasting change in the severity of malaria in mice infected with Plasmodium yoelii; while for several years mice obtained from a specific production suite of a specific commercial vendor were able to clear the parasites effectively in a relatively short time, mice subsequently shipped from the same unit suffered much more severe disease. Gut microbiota analysis of frozen cecal samples identified a distinct and lasting shift in bacteria populations that coincided with the altered response of the later shipments of mice to infection with malaria parasites. Germ-free mice colonized with cecal microbiota from mice within the same production suite before and after this change followed by Plasmodium infection provided a direct demonstration that the change in gut microbiota profoundly impacted the severity of malaria. Moreover, spatial changes in gut microbiota composition were also shown to alter the acute bacterial burden following Salmonella infection, and tumor burden in a lung tumorigenesis model. Conclusion These changes in gut bacteria may have impacted the experimental reproducibility of diverse research groups and highlight the need for both laboratory animal providers and researchers to collaborate in determining the methods and criteria needed to stabilize the gut microbiota of animal breeding colonies and research cohorts, and to develop a microbiota solution to increase experimental rigor and reproducibility.

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“…Moreover, anti-PD-1 therapy redirected macrophages from an M2- to an M1-like phenotype [70]. Paradoxically, intratracheal administration of IL-10 suppressed lung tumorigenesis caused by activated K-ras G12D mutation, together with a dramatic M1 to M2 phenotypic change in IMs [71]. M2-polarized IMs suppressed Th17 functions, which is critical for lung tumorigenesis.…”

Section: Strategies To Use Intrapulmonary Macrophages As a Weapon mentioning

confidence: 99%

Lung Macrophages: Multifunctional Regulator Cells for Metastatic Cells

Mukaida

Nosaka

Nakamoto

et al. 2018

IJMS

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Metastasis is responsible for most of the cancer-associated deaths and proceeds through multiple steps. Several lines of evidence have established an indispensable involvement of macrophages present at the primary tumor sites in various steps of metastasis, from primary tumor growth to its intravasation into circulation. The lungs encompass a large, dense vascular area and, therefore, are vulnerable to metastasis, particularly, hematogenous ones arising from various types of neoplasms. Lung tissues constitutively contain several types of tissue-resident macrophages and circulating monocytes to counteract potentially harmful exogenous materials, which directly reach through the airway. Recent advances have provided an insight into the ontogenetic, phenotypic, and functional heterogeneity of these lung macrophage and monocyte populations, under resting and inflammatory conditions. In this review, we discuss the ontogeny, trafficking dynamics, and functions of these pulmonary macrophages and monocytes and their potential roles in lung metastasis and measures to combat lung metastasis by targeting these populations.

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Inhaled IL-10 Suppresses Lung Tumorigenesis via Abrogation of Inflammatory Macrophage–Th17 Cell Axis

Cited by 29 publications

References 39 publications

Targeting ST2 expressing activated regulatory T cells in Kras-mutant lung cancer

Targeting ST2 expressing activated regulatory T cells in Kras-mutant lung cancer

Temporospatial shifts within commercial laboratory mouse gut microbiota impact experimental reproducibility

Lung Macrophages: Multifunctional Regulator Cells for Metastatic Cells

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