High-Dimensional Analysis Delineates Myeloid and Lymphoid Compartment Remodeling during Successful Immune-Checkpoint Cancer Therapy

Gubin, Matthew M.; Esaulova, Ekaterina; Ward, Jeffrey P.; Malkova, Olga; Runci, Daniele; Wong, Pamela; Noguchi, Takuro; Arthur, Cora D.; Meng, Wei; Alspach, Elise; Medrano, Ruan F.V.; Fronick, Catrina C.; Fehlings, Michael G.; Newell, Evan W.; Fulton, Robert S.; Sheehan, Kathleen C. F.; Oh, Stephen T.; Schreiber, Robert D.; Artyomov, Maxim N.

doi:10.1016/j.cell.2018.11.003

Cited by 97 publications

(120 citation statements)

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“…In agreement with our present work, these emerging studies suggest that TAMs may adapt to a variety of tumor microenvironmental clues during tumor development, by acquiring a large spectrum of states. 32 Importantly, recent studies have shown that the use of immune checkpoint inhibitors such as anti-PD-1 and anti-CTLA-4 can modify the myeloid high-dimensional landscape in mouse models, 33,34 providing new insights into its mechanisms of action and its clinical applications.…”

Section: Discussionmentioning

confidence: 99%

CD163⁺ tumor‐associated macrophage accumulation in breast cancer patients reflects both local differentiation signals and systemic skewing of monocytes

et al. 2020

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Objectives The accumulation of tumor‐associated macrophages (TAMs) is correlated with poor clinical outcome, but the mechanisms governing their differentiation from circulating monocytes remain unclear in humans. Methods Using multicolor flow cytometry, we evaluated TAMs phenotype in 93 breast cancer (BC) patients. Furthermore, monocytes from healthy donors were cultured in the presence of supernatants from dilacerated primary tumors to investigate their differentiation into macrophages (MΦ) in vitro. Additionally, we used transcriptomic analysis to evaluate BC patients’ blood monocytes profiles. Results We observed that high intra‐tumor CD163‐expressing TAM density is predictive of reduced survival in BC patients. In vitro, M‐CSF, TGF‐β and VEGF from primary tumor supernatants skewed the differentiation of healthy donor blood monocytes towards CD163highCD86lowIL‐10high M2‐like MΦ that strongly suppressed CD4+ T‐cell expansion via PD‐L1 and IL‐10. In addition, blood monocytes from about 40% of BC patients displayed an altered response to in vitro stimulation, being refractory to type‐1 MΦ (M1‐MΦ) differentiation and secreting higher amounts of immunosuppressive, metastatic‐related and angiogenic cytokines. Aside from showing that monocyte transcriptome is significantly altered by the presence of BC, we also demonstrated an overall metabolic de‐activation in refractory monocytes of BC patients. In contrast, monocytes from sensitive BC patients undergoing normal M1‐MΦ differentiation showed up‐regulation of IFN‐response genes and had no signs of metabolic alteration. Conclusion Altogether, our results suggest that systemic factors skew BC patient blood monocytes towards a pro‐metastatic profile, resulting in the accumulation of further polarised CD163high TAMs resembling type‐2 MΦ (M2‐MΦ) in the local BC microenvironment. These data indicate that monitoring circulating monocytes in BC patients may provide an indication of early systemic alterations induced by cancer and, thus, be instrumental in the development of improved personalised immunotherapeutic interventions.

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Section: Discussionmentioning

confidence: 99%

CD163⁺ tumor‐associated macrophage accumulation in breast cancer patients reflects both local differentiation signals and systemic skewing of monocytes

et al. 2020

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“…53 The study, however, concluded that the functional and structural diversity of macrophages within the tumor microenvironment reflects mostly to the activation and polarization of infiltrating monocyte subpopulations, rather than of preexisting, intratumoral macrophages. 53 In this review, we describe TAM functions, their involvement in cancer metastasis and response to cytotoxic chemotherapy, all from the viewpoint of their spatiotemporal localization within the tumor microenvironment, rather than their polarization status.…”

Section: Polarization Schemes Of Tams-oversimplification or Not?mentioning

confidence: 98%

“…50 However, even this subcategorization still may not fully describe the continuum of TAM phenotypes observed, and, although still widely accepted, due to convenience for understanding macrophage-related diseases, the M1/M2 dichotomy is increasingly viewed as too bipolar and oversimplified. 51,52 In one of the most comprehensive studies to-date, Gubin et al (2018), performed RNAseq and CyTOF analyses of immune cell populations in the tumor microenvironment and defined 5 categories (based on gene-expression profiling), and 8 categories (based on protein-expression profiling) of monocytes/macrophages that could be distinguished by the markers CD206, CX3CR1, CD1d, and iNOS. 53 The study, however, concluded that the functional and structural diversity of macrophages within the tumor microenvironment reflects mostly to the activation and polarization of infiltrating monocyte subpopulations, rather than of preexisting, intratumoral macrophages.…”

Section: Polarization Schemes Of Tams-oversimplification or Not?mentioning

confidence: 99%

“…51,52 In one of the most comprehensive studies to-date, Gubin et al (2018), performed RNAseq and CyTOF analyses of immune cell populations in the tumor microenvironment and defined 5 categories (based on gene-expression profiling), and 8 categories (based on protein-expression profiling) of monocytes/macrophages that could be distinguished by the markers CD206, CX3CR1, CD1d, and iNOS. 53 The study, however, concluded that the functional and structural diversity of macrophages within the tumor microenvironment reflects mostly to the activation and polarization of infiltrating monocyte subpopulations, rather than of preexisting, intratumoral macrophages. 53 In this review, we describe TAM functions, their involvement in cancer metastasis and response to cytotoxic chemotherapy, all from the viewpoint of their spatiotemporal localization within the tumor microenvironment, rather than their polarization status.…”

Section: Polarization Schemes Of Tams-oversimplification or Not?mentioning

confidence: 99%

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The emerging roles of macrophages in cancer metastasis and response to chemotherapy

Sanchez

Borriello

Entenberg

et al. 2019

Journal of Leukocyte Biology

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Macrophages represent a heterogeneous group of cells, capable of carrying out distinct functions in a variety of organs and tissues. Even within individual tissues, their functions can vary with location. Tumor‐associated macrophages (TAMs) specialize into three major subtypes that carry out multiple tasks simultaneously. This is especially true in the context of metastasis, where TAMs establish most of the cellular and molecular prerequisites for successful cancer cell dissemination and seeding to the secondary site. Perivascular TAMs operate in the perivascular niche, where they promote tumor angiogenesis and aid in the assembly of intravasation sites called tumor microenvironment of metastasis (TMEM). Streaming TAMs co‐migrate with tumor cells (irrespective of the perivascular niche) and promote matrix remodeling, tumor cell invasiveness, and an immunosuppressive local microenvironment. Premetastatic TAMs are recruited to the premetastatic niche, where they can assist in tumor cell extravasation, seeding, and metastatic colonization. The dynamic interplay between TAMs and tumor cells can also modify the ability of the latter to resist cytotoxic chemotherapy (a phenotype known as environment‐mediated drug resistance) and induce chemotherapy‐mediated pro‐metastatic microenvironmental changes. These observations suggest that future therapeutics should be designed to target TAMs with the aim of suppressing the metastatic potential of tumors and rendering chemotherapy more efficient.

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“…In recent years, a common framework for macrophage activation has been suggested that considers a set of surface and genetic markers including CD206 as an "M2 marker" and CD86 as an "M1 marker" (14). Recent technological advances, however, including single cell RNA sequencing (scRNAseq) and mass cytometry suggest that archetypal in vitro phenotypes rarely overlap with those found in physiological conditions (15,16). These approaches open the door to the refined characterization of macrophage populations that reflects the complexity of their phenotype and function in normal and pathological environments.…”

Section: Introductionmentioning

confidence: 99%

Single cell RNA-seq in regenerative and fibrotic biomaterial environments defines new macrophage subsets

Sommerfeld

Cherry

Schwab

et al. 2019

Preprint

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Macrophages play diverse roles in the immune response to infection, cancer, and wound healing where they respond to local environmental signals, yet identification and phenotypic characterization of functional subsets in vivo remains limited. We performed single cell RNA sequencing analysis on differentiated macrophages sorted from a biologic matrix-induced regenerative environment versus a synthetic biomaterial foreign body response (FBR), characterized by TH2/interleukin (IL)-4 and TH17/IL-17, respectively. In the regenerative environment, unbiased clustering and pseudotime analysis revealed distinct macrophage subsets responsible for antigen presentation, chemoattraction, and phagocytosis, as well as a small population with expression profiles of both dendritic cells and skeletal muscle. In the FBR environment, we identified a CD9 hi+ IL-36 + macrophage subset that expressed TH17-associated molecules characteristic of certain auto-immune responses that were virtually absent in mice lacking the IL-17 receptor. Surface marker combinations including CD9 and CD301b defined macrophage fibrotic and regenerative subsets enabling functional assessment and identification in human tissue. Application of the terminal macrophage subsets to train the SingleCellNet algorithm and comparison to human and mouse macrophages in tumor, lung, and liver suggest broad relevance of macrophage classification. These distinct macrophage subsets demonstrate previously unrecognized myeloid phenotypes involved in different tissue responses and provide new targets for potential therapeutic modulation of certain pathologic states and tissue repair.

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High-Dimensional Analysis Delineates Myeloid and Lymphoid Compartment Remodeling during Successful Immune-Checkpoint Cancer Therapy

Cited by 97 publications

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CD163⁺ tumor‐associated macrophage accumulation in breast cancer patients reflects both local differentiation signals and systemic skewing of monocytes

CD163⁺ tumor‐associated macrophage accumulation in breast cancer patients reflects both local differentiation signals and systemic skewing of monocytes

The emerging roles of macrophages in cancer metastasis and response to chemotherapy

Single cell RNA-seq in regenerative and fibrotic biomaterial environments defines new macrophage subsets

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High-Dimensional Analysis Delineates Myeloid and Lymphoid Compartment Remodeling during Successful Immune-Checkpoint Cancer Therapy

Cited by 97 publications

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CD163+ tumor‐associated macrophage accumulation in breast cancer patients reflects both local differentiation signals and systemic skewing of monocytes

CD163+ tumor‐associated macrophage accumulation in breast cancer patients reflects both local differentiation signals and systemic skewing of monocytes

The emerging roles of macrophages in cancer metastasis and response to chemotherapy

Single cell RNA-seq in regenerative and fibrotic biomaterial environments defines new macrophage subsets

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Product

Resources

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CD163⁺ tumor‐associated macrophage accumulation in breast cancer patients reflects both local differentiation signals and systemic skewing of monocytes

CD163⁺ tumor‐associated macrophage accumulation in breast cancer patients reflects both local differentiation signals and systemic skewing of monocytes