Lung fibroblasts facilitate pre-metastatic niche formation by remodeling the local immune microenvironment

Gong, Zheng; Li, Qing; Shi, Jiayuan; Wei, Jian; Li, Peishan; Chang, Chih-Hao; Shultz, Leonard D.; Ren, Guangwen

doi:10.1016/j.immuni.2022.07.001

Cited by 82 publications

(56 citation statements)

References 88 publications

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“…Using a modified experimental lung metastasis model (fig. S6C), in which luciferase-labeled tumor cells were intravenously injected into orthotopic tumor–bearing mice, hence the role of premetastatic niche can be evaluated ( 14 , 43 ), we found that the strong host inflammation condition (primary AT3- gcsf tumors) was superior to the weak one (primary AT3 tumors) in accommodating colonization of AT3-Luc cells (Fig. 3H, left).…”

Section: Resultsmentioning

confidence: 93%

“…8, B and C). In the modified experimental metastasis model in which the functions of premetastatic niches can be gauged ( 14 , 43 ), Ptgs2 ΔMCs mice developed a lower level of lung metastasis than did their WT littermates, whereas the primary tumor growth was not altered by Ptgs2 cKO (fig. S12C).…”

Section: Resultsmentioning

confidence: 99%

“…Next, we attempted to pharmacologically block the PTGS2 (prostaglandin-endoperoxide synthase 2)/PGE 2 signaling pathway as an endeavor to develop clinically applicable approaches to treat lung metastasis. As we recently reported, however, the U.S. Food and Drug Administration (FDA)–approved PTGS2 [cyclooxygenase-2 (COX-2)] inhibitor celecoxib failed to reduce lung tissue–resident PGE 2 levels and alleviate lung metastasis ( 43 ). We then reasoned that the ineffectiveness of PTGS2 inhibition, which was similarly reported in recent breast cancer clinical trials ( 61 – 64 ), might be due to a compensatory effect from COX-1, another isoform of COX (PTGS) ( 65 ).…”

Section: Resultsmentioning

confidence: 99%

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Immunosuppressive reprogramming of neutrophils by lung mesenchymal cells promotes breast cancer metastasis

Gong

Shi

et al. 2023

Sci. Immunol.

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Neutrophils, the most abundant innate immune cells, function as crucial regulators of the adaptive immune system in diverse pathological conditions, including metastatic cancer. However, it remains largely unknown whether their immunomodulatory functions are intrinsic or acquired within the pathological tissue environment. Here, using mouse models of metastatic breast cancer in the lungs, we show that, although neutrophils isolated from bone marrow (BM) or blood are minimally immunosuppressive, lung-infiltrating neutrophils are robustly suppressive of both T cells and natural killer (NK) cells. We found that this tissue-specific immunosuppressive capacity of neutrophils exists in the steady state and is reinforced by tumor-associated inflammation. Acquisition of potent immunosuppression activity by lung-infiltrating neutrophils was endowed by the lung-resident stroma, specifically CD140a + mesenchymal cells (MCs) and largely via prostaglandin-endoperoxide synthase 2 (PTGS2), the rate-limiting enzyme for prostaglandin E 2 (PGE 2 ) biosynthesis. MC-specific deletion of Ptgs2 or pharmacological inhibition of PGE 2 receptors reversed lung neutrophil–mediated immunosuppression and mitigated lung metastasis of breast cancer in vivo. These lung stroma–targeting strategies substantially improved the therapeutic efficacy of adoptive T cell–based immunotherapy in treating metastatic disease in mice. Collectively, our results reveal that the immunoregulatory effects of neutrophils are induced by tissue-resident stroma and that targeting tissue-specific stromal factors represents an effective approach to boost tissue-resident immunity against metastatic disease.

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Section: Resultsmentioning

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Immunosuppressive reprogramming of neutrophils by lung mesenchymal cells promotes breast cancer metastasis

Gong

Shi

et al. 2023

Sci. Immunol.

Self Cite

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“…Indeed, lung fibroblast-derived PGE2 promotes monocyte production of anti-inflammatory IL-10 ( 89 ), and intestinal fibroblast-derived PGE2 inhibits the development of inflammatory macrophages ( 90 ). More recently, a study investigating PGE2 production in fibroblasts across tissues (including intestine but not skin) found that lung fibroblasts secrete significantly more PGE2 compared to fibroblasts from to other tissues ( 91 ). Further, this report demonstrated that lung fibroblasts use PGE2 to suppress dendritic cell antigen presentation.…”

Section: The Immune Effector Functions Of Fibroblastsmentioning

confidence: 99%

“…Specifically, a Sca-1 + CD44 + fibroblast subset recruit and activate neutrophils using C3a, thereby creating a niche for metastasis ( 70 ). Pdgfra + fibroblast Ptgs2 also promotes metastasis ( 91 ). In terms of immunosuppression, it was recently observed that mice with a Twist2 + fibroblast-specific deletion of Ryk (co-receptor for Wnt) develop spontaneous lung inflammation ( 136 ).…”

Section: Evidence Of Fibroblast Immune Function In Vivomentioning

confidence: 99%

Essential immune functions of fibroblasts in innate host defense

Cavagnero

Gallo

2022

Front. Immunol.

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The term fibroblast has been used generally to describe spindle-shaped stromal cells of mesenchymal origin that produce extracellular matrix, establish tissue structure, and form scar. Current evidence has found that cells with this morphology are highly heterogeneous with some fibroblastic cells actively participating in both innate and adaptive immune defense. Detailed analysis of barrier tissues such as skin, gut, and lung now show that some fibroblasts directly sense pathogens and other danger signals to elicit host defense functions including antimicrobial activity, leukocyte recruitment, and production of cytokines and lipid mediators relevant to inflammation and immunosuppression. This review will synthesize current literature focused on the innate immune functions performed by fibroblasts at barrier tissues to highlight the previously unappreciated importance of these cells in immunity.

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Development of an algorithm for biomedical image analysis of the spatial organization of collagen in breast cancer tissue of patients with different clinical status

Lukianova,

Mushii,

Zadvornyi

et al. 2024

FEBS Open Bio

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Collagen, the main component of the tumor microenvironment, plays a key role in the development of breast cancer (BCa); however, the specific changes in its spatial organization during tumor progression have not been definitively elucidated. The existing and available methods for assessing the morphometric parameters of the stroma's fibrous component are insufficient for a detailed description of the state of collagen fibers and for assessing its changes to evaluate the aggressiveness of the BCa course. The aim of the work was to develop an algorithm for microphoto analysis to assess the spatial organization of collagen in BCa tissue of patients with different clinical statuses. The study was conducted on 60 tissue samples of stage I‐II BCa. The processed images were analyzed using the software packages CurveAlign v4.0 and imagej. We established that the increase in BCa stage and the decrease in tumor differentiation grade are associated with decreased length, width, and straightness of collagen fibers, as well as their increased density. The formation of an aggressive basal molecular BCa subtype was accompanied by an increase in tumor‐stroma ratio. The obtained results indicate the possibility of practical application of the developed algorithm for evaluating the spatial organization of collagen in BCa tissue to predict the aggressiveness of the disease course.

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Lung fibroblasts facilitate pre-metastatic niche formation by remodeling the local immune microenvironment

Cited by 82 publications

References 88 publications

Immunosuppressive reprogramming of neutrophils by lung mesenchymal cells promotes breast cancer metastasis

Immunosuppressive reprogramming of neutrophils by lung mesenchymal cells promotes breast cancer metastasis

Essential immune functions of fibroblasts in innate host defense

Development of an algorithm for biomedical image analysis of the spatial organization of collagen in breast cancer tissue of patients with different clinical status

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