Tissue-resident macrophages provide a pro-tumorigenic niche to early NSCLC cells

Casanova-Acebes, María; Dalla, Erica; Leader, Andrew M.; LeBérichel, Jessica; Nikolić, Jovan; Morales, Blanca M.; Brown, Markus; Chang, Christie; Troncoso, Leanna; Chen, Shuo; Sastre-Perona, Ana; Park, Matthew D.; Tabachnikova, Alexandra; Dhainaut, Maxime; Hamon, Pauline; Maier, Bárbara; Sawai, Catherine M.; Agullo‐Pascual, Esperanza; Schöber, Markus; Brown, Brian D.; Reizis, Boris; Marron, Thomas U.; Kenigsberg, Ephraim; Moussion, Christine; Benaroch, Philippe; Aguirre‐Ghiso, Julio A.; Mérad, Miriam

doi:10.1038/s41586-021-03651-8

Cited by 373 publications

(343 citation statements)

References 47 publications

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“…Self-renewing tissueresident macrophages are seeded during embryonic development [6][7][8][9][10] , while inflammatory stimuli prompt infiltration of adult hematopoietic stem cell-derived monocytes that give rise to tumor macrophages [11][12][13][14] . These monocyte-derived macrophages preferentially accumulate as tumors progress 15 and may predominate in regulating the ongoing antitumor T cell response 16 .…”

Section: Introductionmentioning

confidence: 99%

Holistic Characterization of Tumor Monocyte-to-Macrophage Differentiation Integrates Distinct Immune Phenotypes in Kidney Cancer

Rao

et al. 2021

Preprint

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The tumor immune microenvironment (TIME) is commonly infiltrated by diverse collections of myeloid cells. Yet, the complexity of myeloid cell identity and plasticity has challenged efforts to define bona fide populations and determine their connections to T cell function and their relation to patient outcome. Here we leverage single-cell RNA-sequencing (scRNA-seq) analysis of several mouse and human tumors and find that monocyte-macrophage diversity is characterized by a combination of conserved lineage states as well as transcriptional programs accessed along the differentiation trajectory. Using mouse models, we also find that tumor monocyte-to-macrophage progression is profoundly tied to regulatory T cell (Treg) abundance. Importantly, in human kidney cancer, heterogeneity in macrophage accumulation and myeloid composition corresponded to variance in, not only Treg density, but also the quality of infiltrating CD8+ T cells. In this way, holistic analysis of monocyte-to-macrophage differentiation creates a framework for critically different immune states in kidney tumors.

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Section: Introductionmentioning

confidence: 99%

Holistic Characterization of Tumor Monocyte-to-Macrophage Differentiation Integrates Distinct Immune Phenotypes in Kidney Cancer

Rao

et al. 2021

Preprint

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“…At these early timepoints, immune infiltration in the tumors is primarily from myeloid lineages, with tissue-resident and newly-recruited components. While our 3D system does not recapitulate all influential immune components, such as dendritic cells [57], there is strong evidence that macrophages play a key role in generating a pro-tumoral niche [3,11]. Here, we found that with a relatively simple 3-cell type reconstruction of the TME, we were able to capture a macrophage immunosuppressive transition and see them acquire a phenotypic and functional profile similar to that of TAMs isolated directly from growing melanoma tumors.…”

Section: Discussionmentioning

confidence: 83%

“…Non-tumor cell types within the milieu co-evolve with tumor cells, disrupting tissue homeostasis while favoring disease progression and metastasis [2]. Thus, cell-cell interactions between immune cells, tumor cells, and other support cells play an active role in shaping the immune environment in tumor progression and responses to immunotherapy [3].…”

Section: Introductionmentioning

confidence: 99%

“…On the other hand, advanced melanomas usually display low infiltration of T cells and high numbers of tumor-associated myeloid cells (TAMs), and the latter correlates with a worse prognosis [6]. TAMs and cancerassociated fibroblasts (CAFs) are key players in the TME, providing support for both tumor and immune cells depending on the context [3,7]. TAMs reprogram their functional state as the tumor grows, although the specific mechanisms leading to the accumulation of immunosuppressive TAMs remain unclear.…”

Section: Introductionmentioning

confidence: 99%

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3D Model of the Early Melanoma Microenvironment Captures Macrophage Transition into a Tumor-Promoting Phenotype

Pizzurro

Liu

Bridges

et al. 2021

Cancers

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Tumor immune response is shaped by the tumor microenvironment (TME), which often evolves to be immunosuppressive, promoting disease progression and metastasis. An important example is melanoma tumors, which display high numbers of tumor-associated macrophages (TAMs) that are immunosuppressive but also have the potential to restore anti-tumor activity. However, to therapeutically target TAMs, there is a need to understand the early events that shape their tumor-promoting profile. To address this, we built and optimized 3D in vitro co-culture systems, composed of a collagen-I matrix scaffolding murine bone-marrow-derived macrophages (BMDMs), YUMM1.7 melanoma cells, and fibroblasts to recreate the early melanoma TME and study how interactions with fibroblasts and tumor cells modulate macrophage immune activity. We monitored BMDM behavior and interactions through time-lapse imaging and characterized their activation and secretion. We found that stromal cells induced a rapid functional activation, with increased motility and response from BMDMs. Over the course of seven days, BMDMs acquired a phenotype and secretion profile that resembled melanoma TAMs in established tumors. Overall, the direct cell–cell interactions with the stromal components in a 3D environment shape BMDM transition to a TAM-like immunosuppressive state. Our systems will enable future studies of changes in macrophage–stromal cross-talk in the melanoma TME

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“…Others have shown that tissue-resident macrophages may play an equally important role in contributing to the TAM population. In non-small cell lung cancer (NSCLC), tissue resident macrophages provide a pro-tumorigenic niche to early NSCLC cells [ 18 ]. Zhu et al identified both inflammatory monocytes and tissue-resident macrophages as sources of TAMs with monocyte-derived TAMs playing more important roles in antigen presentation and embryonic-derived TAMs exhibiting a more pro-fibrotic profile [ 19 ].…”

Section: Macrophage and Tamsmentioning

confidence: 99%

Targeting Tumor-Associated Macrophages in Cancer Immunotherapy

Petty

Owen

Yang

et al. 2021

Cancers

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Tumor-associated macrophages (TAMs) represent the most abundant leukocyte population in most solid tumors and are greatly influenced by the tumor microenvironment. More importantly, these macrophages can promote tumor growth and metastasis through interactions with other cell populations within the tumor milieu and have been associated with poor outcomes in multiple tumors. In this review, we examine how the tumor microenvironment facilitates the polarization of TAMs. Additionally, we evaluate the mechanisms by which TAMs promote tumor angiogenesis, induce tumor invasion and metastasis, enhance chemotherapeutic resistance, and foster immune evasion. Lastly, we focus on therapeutic strategies that target TAMs in the treatments of cancer, including reducing monocyte recruitment, depleting or reprogramming TAMs, and targeting inhibitory molecules to increase TAM-mediated phagocytosis.

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Tissue-resident macrophages provide a pro-tumorigenic niche to early NSCLC cells

Cited by 373 publications

References 47 publications

Holistic Characterization of Tumor Monocyte-to-Macrophage Differentiation Integrates Distinct Immune Phenotypes in Kidney Cancer

Holistic Characterization of Tumor Monocyte-to-Macrophage Differentiation Integrates Distinct Immune Phenotypes in Kidney Cancer

3D Model of the Early Melanoma Microenvironment Captures Macrophage Transition into a Tumor-Promoting Phenotype

Targeting Tumor-Associated Macrophages in Cancer Immunotherapy

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