The parallel lives of angiogenesis and immunosuppression: cancer and other tales

Motz, Gregory T.; Coukos, George

doi:10.1038/nri3064

Cited by 414 publications

(377 citation statements)

References 139 publications

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“…Burnet's "immune surveillance of cancer" theory has been revised to accommodate leukocyte subsets, both of myeloid and lymphoid origin, that enhance cancer cell proliferation (1,41). The data presented here add to this revised model by identifying and characterizing a population of IL-17-secreting γδ T cells that has the potential to promote ID8 ovarian tumor growth, thus effectively overriding the antitumor function of coexisting IFN-γ-producing γδ T cells.…”

Section: Discussionmentioning

confidence: 98%

Murine CD27 ⁽⁻⁾ Vγ6 ⁽⁺⁾ γδ T cells producing IL-17A promote ovarian cancer growth via mobilization of protumor small peritoneal macrophages

Rei

Gonçalves-Sousa

Lança

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

184

199

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Cancer-associated inflammation mobilizes a variety of leukocyte populations that can inhibit or enhance tumor cell growth in situ. These subsets include γδ T cells, which can infiltrate tumors and typically provide large amounts of antitumor cytokines, such as IFN-γ. By contrast, we report here that in a well-established transplantable (ID8 cell line) model of peritoneal/ovarian cancer, γδ T cells promote tumor cell growth. γδ T cells accumulated in the peritoneal cavity in response to tumor challenge and could be visualized within solid tumor foci. Functional characterization of tumor-associated γδ T cells revealed preferential production of interleukin-17A (IL-17), rather than IFN-γ. Consistent with this finding, both T cell receptor (TCR)δ-deficient and IL-17-deficient mice displayed reduced ID8 tumor growth compared with wild-type animals. IL-17 production by γδ T cells in the tumor environment was essentially restricted to a highly proliferative CD27 (−) subset that expressed Vγ6 instead of the more common Vγ1 and Vγ4 TCR chains. The preferential expansion of IL-17-secreting CD27 (−) Vγ6 (+) γδ T cells associated with the selective mobilization of unconventional small peritoneal macrophages (SPMs) that, in comparison with large peritoneal macrophages, were enriched for IL-17 receptor A, and for protumor and proangiogenic molecular mediators, which were upregulated by IL-17. Importantly, SPMs were uniquely and directly capable of promoting ovarian cancer cell proliferation. Collectively, this work identifies an IL-17-dependent lymphoid/myeloid crosstalk involving γδ T cells and SPMs that promotes tumor cell growth and thus counteracts cancer immunosurveillance. gamma-delta T cells | tumor immunologyD eveloping tumors are infiltrated by a variety of leukocyte subsets that can either promote or inhibit inflammation, and thus impact on cancer progression (1). Among such populations are γδ T cells, which are major players in lymphoid stress surveillance likely due to their recognition of stress-inducible molecules independently of MHC-mediated antigen presentation (2). Moreover, abundant IFN-γ secretion and cytotoxic effector functions endow γδ T cells with potent antitumor activity. This has been clearly documented in murine models of spontaneous (3), chemically induced (4), transgenic (5), and transplantable (6, 7) tumors. For example, in the widely used B16 melanoma model, γδ T cells were shown to infiltrate tumors very early and provided a critical source of IFN-γ that significantly delayed tumor growth (6, 7).Human γδ T cells also possess IFN-γ-secreting potential, which is displayed immediately at birth (8) and display cytotoxicity against tumor lines of diverse origin, including epithelial (9, 10) and hematological (11,12) tumors. This has prompted the development of cancer clinical trials targeting γδ T cells, which have produced encouraging, albeit highly variable, degrees of therapeutic responses (13-15). There is therefore great interest in maximizing the antitumor functions of γδ T cells for cancer ...

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Section: Discussionmentioning

confidence: 98%

Murine CD27 ⁽⁻⁾ Vγ6 ⁽⁺⁾ γδ T cells producing IL-17A promote ovarian cancer growth via mobilization of protumor small peritoneal macrophages

Rei

Gonçalves-Sousa

Lança

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

184

199

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“…On the other hand, a growing body of research in mouse cancer models has now implicated multiple leukocyte species as causal players in cancer initiation and progression. For example, macrophages and granulocytes are known to generate an “inflammatory” tumor microenvironment that promotes angiogenesis and ECM remodeling, enhances tumor cell motility and invasion, and suppresses antitumor adaptive immune responses (Mantovani et al., 2008; Motz and Coukos, 2011; Murdoch et al., 2008; Qian and Pollard, 2010; Squadrito and De Palma, 2011). For these reasons, tumor‐promoting inflammation is now regarded as an enabling characteristic of cancer (Hanahan and Weinberg, 2011).…”

Section: Variability and Dynamics Of Stromal Cell Componentsmentioning

confidence: 99%

The biology of personalized cancer medicine: Facing individual complexities underlying hallmark capabilities

2012

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It is a time of great promise and expectation for the applications of knowledge about mechanisms of cancer toward more effective and enduring therapies for human disease. Conceptualizations such as the hallmarks of cancer are providing an organizing principle with which to distill and rationalize the abject complexities of cancer phenotypes and genotypes across the spectrum of the human disease. A countervailing reality, however, involves the variable and often transitory responses to most mechanism‐based targeted therapies, returning full circle to the complexity, arguing that the unique biology and genetics of a patient's tumor will in the future necessarily need to be incorporated into the decisions about optimal treatment strategies, the frontier of personalized cancer medicine. This perspective highlights considerations, metrics, and methods that may prove instrumental in charting the landscape of evaluating individual tumors so to better inform diagnosis, prognosis, and therapy. Integral to the consideration is remarkable heterogeneity and variability, evidently embedded in cancer cells, but likely also in the cell types composing the supportive and interactive stroma of the tumor microenvironment (e.g., leukocytes and fibroblasts), whose diversity in form, regulation, function, and abundance may prove to rival that of the cancer cells themselves. By comprehensively interrogating both parenchyma and stroma of patients' cancers with a suite of parametric tools, the promise of mechanism‐based therapy may truly be realized.

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“…Intratumoral Tregs secrete high levels of VEGF, suggesting that they may directly contribute to angiogenesis and tumor growth [65,70]. In addition, Tregs might promote angiogenesis via an indirect cellular circuitry as they inhibit Th1 effector T cells, which normally produce antiangiogenic cytokines (IFN-γ) and chemokines (CXCL9, CXCL11) [64].…”

Section: Tregs and Angiogenesismentioning

confidence: 99%

Tumor-Infiltrating Regulatory T Cells: Phenotype, Role, Mechanism of Expansion In Situ and Clinical Significance

Tanchot

Terme

Péré

et al. 2012

Cancer Microenvironment

119

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In immunocompetent individuals, the immune system initially eradicates potentially tumorigenic cells as they develop, a capacity that is progressively lost when malignant cells acquire alterations that sustain immunosubversion and/or immunoevasion. One of the major mechanisms whereby cancer cells block antitumor immune responses involves a specific class of immunosuppressive T cells that-in the vast majority of cases-express the Forkhead box P3 (FOXP3) transcription factor. Such FOXP3 + regulatory T cells (Tregs) accumulate within neoplastic lesions as a result of several distinct mechanisms, including increased infiltration, local expansion, survival advantage and in situ development from conventional CD4 + cells.

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The parallel lives of angiogenesis and immunosuppression: cancer and other tales

Cited by 414 publications

References 139 publications

Murine CD27 ⁽⁻⁾ Vγ6 ⁽⁺⁾ γδ T cells producing IL-17A promote ovarian cancer growth via mobilization of protumor small peritoneal macrophages

Murine CD27 ⁽⁻⁾ Vγ6 ⁽⁺⁾ γδ T cells producing IL-17A promote ovarian cancer growth via mobilization of protumor small peritoneal macrophages

The biology of personalized cancer medicine: Facing individual complexities underlying hallmark capabilities

Tumor-Infiltrating Regulatory T Cells: Phenotype, Role, Mechanism of Expansion In Situ and Clinical Significance

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The parallel lives of angiogenesis and immunosuppression: cancer and other tales

Cited by 414 publications

References 139 publications

Murine CD27 (−) Vγ6 (+) γδ T cells producing IL-17A promote ovarian cancer growth via mobilization of protumor small peritoneal macrophages

Murine CD27 (−) Vγ6 (+) γδ T cells producing IL-17A promote ovarian cancer growth via mobilization of protumor small peritoneal macrophages

The biology of personalized cancer medicine: Facing individual complexities underlying hallmark capabilities

Tumor-Infiltrating Regulatory T Cells: Phenotype, Role, Mechanism of Expansion In Situ and Clinical Significance

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Product

Resources

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Murine CD27 ⁽⁻⁾ Vγ6 ⁽⁺⁾ γδ T cells producing IL-17A promote ovarian cancer growth via mobilization of protumor small peritoneal macrophages

Murine CD27 ⁽⁻⁾ Vγ6 ⁽⁺⁾ γδ T cells producing IL-17A promote ovarian cancer growth via mobilization of protumor small peritoneal macrophages