CD169+ lymph node macrophages have protective functions in mouse breast cancer metastasis

Tacconi, Carlotta; Commerford, Catharina D.; Dieterich, Lothar C.; Schwager, Simon; He, Yuliang; Ikenberg, Kristian; Friebel, Ekaterina; Becher, Burkhard; Tugues, Sònia; Detmar, Michael

doi:10.1016/j.celrep.2021.108993

Cited by 42 publications

(38 citation statements)

References 65 publications

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“…They also found that the capture of tumor-derived exosomes by SMs inhibited the proliferation of pro-tumor B cells in the lymph nodes; an immunohistochemical analysis using human samples revealed the presence of melanoma-derived antigens in melanoma-free draining lymph nodes. Similar effects of SMs on B-cell proliferation in murine 4T1 and MMTV-PyMT mammary carcinoma models were reported by Tacconi et al [28]. These authors demonstrated lung metastasis of cancer cells in SM-depleted mice, but depletion of B cells using an anti-CD20 antibody significantly suppressed lung metastasis.…”

Section: The Function Of Sms In Protumor Function Of B-lymphocytes In Micesupporting

confidence: 79%

Anti-Cancer Immune Reaction and Lymph Node Macrophage; A Review from Human and Animal Studies

Komohara

Anami

Asano

et al. 2021

Immuno

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Lymph nodes are secondary lymphoid organs that appear as bean-like nodules usually <1 cm in size, and they are localized throughout the body. Many antigen-presenting cells such as dendritic cells and macrophages reside in lymph nodes, where they mediate host defense responses against pathogens such as viruses and bacteria. In cancers, antigen-presenting cells induce cytotoxic T lymphocytes (CTLs) to react to cancer cell-derived antigens. Macrophages located in the lymph node sinus are of particular interest in relation to anti-cancer immune responses because many studies using both human specimens and animal models have suggested that lymph node macrophages expressing CD169 play a key role in activating anti-cancer CTLs. The regulation of lymph node macrophages therefore represents a potentially promising novel approach in anti-cancer therapy.

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Section: The Function Of Sms In Protumor Function Of B-lymphocytes In Micesupporting

confidence: 79%

Anti-Cancer Immune Reaction and Lymph Node Macrophage; A Review from Human and Animal Studies

Komohara

Anami

Asano

et al. 2021

Immuno

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“…We demonstrated that SSMs possess anti-tumor activity by showing that in their absence tumors grow faster (8). These observations have been confirmed in additional tumor types (9,10). The analyses above start to narrow down which potential biological processes may be at the root of SSM biology in cancer.…”

Section: Resultssupporting

confidence: 62%

“…We have recently demonstrated that SSMs possess anti-tumor activity because in their absence tumors grow faster ( 8 ). These observations have been confirmed in additional tumor types ( 9 , 10 ). However, the cellular and molecular mechanisms responsible for SSM anti-tumor activity are still unknown.…”

Section: Introductionsupporting

confidence: 60%

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Gene Expression Profiling of Lymph Node Sub-Capsular Sinus Macrophages in Cancer

et al. 2021

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Lymph nodes are key lymphoid organs collecting lymph fluid and migratory cells from the tissue area they survey. When cancerous cells arise within a tissue, the sentinel lymph node is the first immunological organ to mount an immune response. Sub-capsular sinus macrophages (SSMs) are specialized macrophages residing in the lymph nodes that play important roles as gatekeepers against particulate antigenic material. In the context of cancer, SSMs capture tumor-derived extracellular vesicles (tEVs), a form of particulate antigen released in high amounts by tumor cells. We and others have recently demonstrated that SSMs possess anti-tumor activity because in their absence tumors progress faster. A comprehensive profiling of SSMs represents an important first step to identify the cellular and molecular mechanisms responsible for SSM anti-tumor activity. Unfortunately, the isolation of SSMs for molecular analyses is very challenging. Here, we combined an optimized dissociation protocol, careful marker selection and stringent gating strategies to highly purify SSMs. We provide evidence of decreased T and B cell contamination, which allowed us to reveal the gene expression profile of this elusive macrophage subset. Squamous cell carcinomas induced an increase in the expression of Fc receptors, lysosomal and proteasomal enzymes in SSMs. Imaging of mouse and patient lymph nodes confirmed the presence of the top differentially expressed genes. These results suggest that SSMs respond to tumor formation by upregulating the machinery necessary for presentation of tumor particulate antigens to B cells.

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“…In addition, they play a critical role in the initiation of the immune responses against immune complexes and virus [16][17][18] as well as promoting humoral immunity 19,20 . Despite the role of macrophages against infectious pathogens has been largely demonstrated, their involvement in the response against tumor remains somehow controversial [21][22][23][24][25][26][27] . This is mainly due to the ability of these cells to activate either anti-or pro-tumoral responses, according to their cell plasticity, that allows them being dicotomically classified in M1 and M2 macrophages 28,29 .…”

Section: Introductionmentioning

confidence: 99%

IL-1α secreted by subcapsular sinus macrophages promotes melanoma metastasis in the sentinel lymph node by upregulating STAT3 signaling in the tumor

Virgilio

Bordini

Sartori

et al. 2021

Preprint

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During melanoma metastasization, tumor cells originated in the skin migrate via lymphatic vessels to the sentinel lymph node (sLN) in a process that facilitates their spread across the body. Here, we characterized the innate inflammatory responses to melanoma metastasis in the sLN. For this purpose, we confirmed the migration of fluorescent metastatic melanoma cells to the sLN and we characterized the inflammatory response in the metastatic microenvironment. We found that macrophages located in the subcapsular sinus (SSM), produce pro-tumoral IL-1α after recognition of tumor antigens. Moreover, we confirmed that the administration of an anti-IL-1α depleting antibody reduced metastasis. Conversely, the administration of recombinant IL-1α accelerated the lymphatic spreading of the tumor. Additionally, the elimination of the macrophages significantly reduced the progression of the metastatic spread. To understand the mechanism of action of IL-1α in the context of the lymph node microenvironment, we applied single-cell RNA sequencing to dissected metastases obtained from animals treated with an anti-IL-1α blocking antibody. Amongst the different pathways affected, we identified STAT3 as one of the main targets of IL-1α signaling in metastatic cells. Moreover, we found that the anti-IL-1α anti-tumoral effect was not mediated by lymphocytes, as IL-1R1 KO mice did not show any improvement in metastasis growth. Finally, we found a synergistic anti-metastatic effect of the combination of IL-1α blocking and the STAT3 inhibitor (STAT3i) stattic. In summary, we described a new mechanism by which SSM support melanoma metastasis, highlighting a new target for immunotherapy.

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CD169+ lymph node macrophages have protective functions in mouse breast cancer metastasis

Cited by 42 publications

References 65 publications

Anti-Cancer Immune Reaction and Lymph Node Macrophage; A Review from Human and Animal Studies

Anti-Cancer Immune Reaction and Lymph Node Macrophage; A Review from Human and Animal Studies

Gene Expression Profiling of Lymph Node Sub-Capsular Sinus Macrophages in Cancer

IL-1α secreted by subcapsular sinus macrophages promotes melanoma metastasis in the sentinel lymph node by upregulating STAT3 signaling in the tumor

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