LIF regulates CXCL9 in tumor-associated macrophages and prevents CD8+ T cell tumor-infiltration impairing anti-PD1 therapy

Pascual-García, Mónica; Bonfill-Teixidor, Ester; Planas‐Rigol, Ester; Rubio-Pérez, Carlota; Iurlaro, Raffaella; Arias, Alexandra; Cuartas, Isabel; Sala-Hojman, Ada; Escudero, Laura; Martínez‐Ricarte, Francisco; Huber-Ruano, Isabel; Nuciforo, Paolo; Pedrosa, Leire; Marques, Carolina; Braña, Irene; Garralda, Elena; Vieito, María; Squatrito, Massimo; Pineda, Estela; Graus, Francesc; Espejo, Carmen; Sahuquillo, Juan; Tabernero, Josep; Seoane, Joan

doi:10.1038/s41467-019-10369-9

Cited by 181 publications

(160 citation statements)

References 40 publications

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“…In addition, in LIF À/À mice mammary gland involution is delayed and reduced apoptosis is seen, while mammary glands show precocious development during pregnancy, indicating that LIF also plays a crucial role in involution following weaning (7). Finally, LIF also has important immunosuppressive functions during embryo implantation by regulating the numbers and migration of macrophages, uterine natural killer cells, and eosinophils (8,9), and similar effects were observed in a very recent study showing that LIF prevents CD8 þ T-cell infiltration into the tumor while at the same time activating protumoral macrophage function in the tumor microenvironment thus enhancing the immunosuppressive nature of the tumor (10).…”

supporting

confidence: 61%

Stem Cell Factor LIFted as a Promising Clinical Target for Cancer Therapy

Shi

Hunter

2019

Molecular Cancer Therapeutics

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supporting

confidence: 61%

Stem Cell Factor LIFted as a Promising Clinical Target for Cancer Therapy

Shi

Hunter

2019

Molecular Cancer Therapeutics

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“…In several tumor models, the pharmacological inhibition of PI3Kγ or the stimulation of NF-κB was able to synergize with ICB therapy to promote tumor regression [49][50][51][52]. Other studies showed that high expression by TAMs of the leukemia inhibitory factor (LIF), a member of the IL-6 family, triggers the epigenetic silencing of CXCL9, a chemo-attractant for CD8+ T cells, and LIF inhibition improved the efficacy of anti-PD-1 therapy [53]. Finally, several studies have described how TAMs also interfere with the correct recruitment and localization of CD8+ T cells within the tumor, thus precluding the efficacy of ICB therapy [54,55].…”

Section: Interaction Of Tams With Immune-checkpoint Blockade Therapymentioning

confidence: 99%

Current Strategies to Target Tumor-Associated-Macrophages to Improve Anti-Tumor Immune Responses

Anfray

Ummarino

Andón

et al. 2019

Cells

240

205

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: Established evidence demonstrates that tumor-infiltrating myeloid cells promote rather than stop-cancer progression. Tumor-associated macrophages (TAMs) are abundantly present at tumor sites, and here they support cancer proliferation and distant spreading, as well as contribute to an immune-suppressive milieu. Their pro-tumor activities hamper the response of cancer patients to conventional therapies, such as chemotherapy or radiotherapy, and also to immunotherapies based on checkpoint inhibition. Active research frontlines of the last years have investigated novel therapeutic strategies aimed at depleting TAMs and/or at reprogramming their tumor-promoting effects, with the goal of re-establishing a favorable immunological anti-tumor response within the tumor tissue. In recent years, numerous clinical trials have included pharmacological strategies to target TAMs alone or in combination with other therapies. This review summarizes the past and current knowledge available on experimental tumor models and human clinical studies targeting TAMs for cancer treatment.

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“…Analogous to CNTF, LIF signals through LIFRa and gp130 to induce JAK/STAT dependent gene transcription. It was first described as a suppressor of proliferation in a myeloid leukemia cell line, but has since been associated to functions in multiple peripheral organs (252)(253)(254)(255)(256)(257). In addition, LIF has been recognized as neuropoetic cytokine, regulating the differentiation and activation of multiple cell types in the CNS (258)(259)(260)(261)(262).…”

Section: Lifmentioning

confidence: 99%

Protective Functions of Reactive Astrocytes Following Central Nervous System Insult

2020

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Astrocytes play important roles in numerous central nervous system disorders including autoimmune inflammatory, hypoxic, and degenerative diseases such as Multiple Sclerosis, ischemic stroke, and Alzheimer's disease. Depending on the spatial and temporal context, activated astrocytes may contribute to the pathogenesis, progression, and recovery of disease. Recent progress in the dissection of transcriptional responses to varying forms of central nervous system insult has shed light on the mechanisms that govern the complexity of reactive astrocyte functions. While a large body of research focuses on the pathogenic effects of reactive astrocytes, little is known about how they limit inflammation and contribute to tissue regeneration. However, these protective astrocyte pathways might be of relevance for the understanding of the underlying pathology in disease and may lead to novel targeted approaches to treat autoimmune inflammatory and degenerative disorders of the central nervous system. In this review article, we have revisited the emerging concept of protective astrocyte functions and discuss their role in the recovery from inflammatory and ischemic disease as well as their role in degenerative disorders. Focusing on soluble astrocyte derived mediators, we aggregate the existing knowledge on astrocyte functions in the maintenance of homeostasis as well as their reparative and tissue-protective function after acute lesions and in neurodegenerative disorders. Finally, we give an outlook of how these mediators may guide future therapeutic strategies to tackle yet untreatable disorders of the central nervous system.

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LIF regulates CXCL9 in tumor-associated macrophages and prevents CD8+ T cell tumor-infiltration impairing anti-PD1 therapy

Cited by 181 publications

References 40 publications

Stem Cell Factor LIFted as a Promising Clinical Target for Cancer Therapy

Stem Cell Factor LIFted as a Promising Clinical Target for Cancer Therapy

Current Strategies to Target Tumor-Associated-Macrophages to Improve Anti-Tumor Immune Responses

Protective Functions of Reactive Astrocytes Following Central Nervous System Insult

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