The Tumor Necrosis Factor Superfamily Member RANKL Suppresses Effector Cytokine Production in Group 3 Innate Lymphoid Cells

Bando, Jennifer K.; Gilfillan, Susan; Song, Christina; McDonald, Keely G.; Huang, Stanley Ching-Cheng; Newberry, Rodney D.; Kobayashi, Yasuhiro; Allan, David; Carlyle, James R.; Cella, Marina; Colonna, Marco

doi:10.1016/j.immuni.2018.04.012

Cited by 70 publications

(47 citation statements)

References 59 publications

(70 reference statements)

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“…14,15 RANK expression on CD11b+ TAMs is associated with CD206 but low MHCII expression, indicative of immunosuppressive M2-type TAMs. 27 Together, these findings support the hypothesis that RANKL, originating from various sources, mediates RANK signalling in TAMCs and immunosuppressive/tolerogenic effects in the TME. [9][10][11] However, RANKL has been reported to be expressed at a generally low frequency overall in mouse TILs (on < 10% of infiltrating T cells, including Ki67+/antigen-experienced T cells), with a higher proportion of CD8 + than CD4 + T cells expressing RANKL.…”

Section: Discussionsupporting

confidence: 74%

“…15 Alternatively, the immunosuppressive RANKL signal may originate from certain lymph node stromal cells [marginal reticular cells (MRCs)], 25 tumor cells themselves, 26 NK cells or ILC3s. 27 Together, these findings support the hypothesis that RANKL, originating from various sources, mediates RANK signalling in TAMCs and immunosuppressive/tolerogenic effects in the TME. The inhibition of immunosuppressive TAMCs and increased TIL infiltration achieved by RANKL/ RANK blockade complements the reversal of CD8 + T-cell dysfunction resulting from PD-1 blockade, leading to an enhanced anti-tumor effect.…”

Section: Discussionsupporting

confidence: 74%

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Retracted: Dual targeting of RANKL and PD‐1 with a bispecific antibody improves anti‐tumor immunity

2019

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Objectives The addition of RANKL/RANK blockade to immune checkpoint inhibitors (ICIs) such as anti‐PD‐1/PD‐L1 and anti‐CTLA4 antibodies is associated with increased anti‐tumor immunity in mice. Recent retrospective clinical studies in patients with advanced melanoma and lung cancer suggest the addition of anti‐RANKL antibody to ICI increases the overall response rate relative to ICI treatment alone. Based on this rationale, we developed a novel bispecific antibody (BsAb) co‐targeting RANKL and PD‐1. Methods We characterized target binding and functional activity of the anti‐RANKL/PD‐1 BsAb in cell‐based assays. Anti‐tumor activity was confirmed in experimental lung metastasis models and in mice with established subcutaneously transplanted tumors. Results The anti‐RANKL/PD‐1 BsAb retained binding to both RANKL and PD‐1 and blocked the interaction with respective counter‐structures RANK and PD‐L1. The inhibitory effect of anti‐RANKL/PD‐1 BsAb was confirmed by demonstrating a complete block of RANKL‐dependent osteoclast formation. Monotherapy activity of anti‐RANKL/PD‐1 BsAb was observed in anti‐PD‐1 resistant tumors and, when combined with anti‐CTLA‐4 mAb, increased anti‐tumor responses. An equivalent or superior anti‐tumor response was observed with the anti‐RANKL/PD‐1 BsAb compared with the combination of parental anti‐RANKL plus anti‐PD‐1 antibodies depending upon the tumor model. Discussion Mechanistically, the anti‐tumor activity of anti‐RANKL/PD‐1 BsAb required CD8+T cells, host PD‐1 and IFNγ. Targeting RANKL and PD‐1 simultaneously within the tumor microenvironment (TME) improved anti‐tumor efficacy compared with combination of two separate mAbs. Conclusion In summary, the bispecific anti‐RANKL/PD‐1 antibody demonstrates potent tumor growth inhibition in settings of ICI resistance and represents a novel modality for clinical development in advanced cancer.

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Section: Discussionsupporting

confidence: 74%

Section: Discussionsupporting

confidence: 74%

Retracted: Dual targeting of RANKL and PD‐1 with a bispecific antibody improves anti‐tumor immunity

2019

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“…The aryl hydrocarbon receptor (AhR) is a metabolite‐sensing nuclear receptor expressed by ILC3, ligands for which are also present in nutritional metabolites and promote ILC3 postnatal expansion and IL‐22 production . While signals inhibiting ILC3 responses remain largely unclear, it was recently shown that engagement of receptor activator of nuclear factor kappa‐Β ligand (RANKL) results in suppression of effector cytokine production …”

Section: Activation and Effector Functions Of Ilcsmentioning

confidence: 99%

Innate lymphoid cells in lung infection and immunity

Stehle

Hernandez

Romagnani

2018

Immunological Reviews

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Summary In recent years, innate lymphoid cells (ILCs) have emerged as key mediators of protection and repair of mucosal surfaces during infection. The lung, a dynamic mucosal tissue that is exposed to a plethora of microbes, is a playground for respiratory infection‐causing pathogens which are not only a major cause of fatalities worldwide, but are also associated with comorbidities and decreased quality of life. The lung provides a rich microenvironment to study ILCs in the context of innate protection mechanisms within the airways, unraveling their distinct functions not only in health but also in disease. In this review, we discuss how pulmonary ILCs play a role in protection against viral, parasitic, bacterial, and fungal challenge, along with the mechanisms underlying this ILC‐mediated immunity.

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“…Loss of RANKL expression in ILC3 in Rorc ‐Cre; Tnfsf11 fl/fl mice led to enhanced IL‐17A and IL‐22 production and hyperresponsive CCR6 + ILC3. Autocrine RANK‐RANKL interactions regulated ILC3 abundance and function in tissues …”

Section: Innate Lymphoid Cellsmentioning

confidence: 99%

Innate lymphoid cells, mediators of tissue homeostasis, adaptation and disease tolerance

Branzk

Gronke

Diefenbach

2018

Immunological Reviews

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Summary Innate lymphoid cells (ILC) are a recently identified group of tissue‐resident innate lymphocytes. Available data support the view that ILC or their progenitors are deposited and retained in tissues early during ontogeny. Thereby, ILC become an integral cellular component of tissues and organs. Here, we will review the intriguing relationships between ILC and basic developmental and homeostatic processes within tissues. Studying ILC has already led to the appreciation of the integral roles of immune cells in tissue homeostasis, morphogenesis, metabolism, regeneration, and growth. This area of immunology has not yet been studied in‐depth but is likely to reveal important networks contributing to disease tolerance and may be harnessed for future therapeutic approaches.

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The Tumor Necrosis Factor Superfamily Member RANKL Suppresses Effector Cytokine Production in Group 3 Innate Lymphoid Cells

Cited by 70 publications

References 59 publications

Retracted: Dual targeting of RANKL and PD‐1 with a bispecific antibody improves anti‐tumor immunity

Retracted: Dual targeting of RANKL and PD‐1 with a bispecific antibody improves anti‐tumor immunity

Innate lymphoid cells in lung infection and immunity

Innate lymphoid cells, mediators of tissue homeostasis, adaptation and disease tolerance

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