Secreted gelsolin inhibits DNGR-1-dependent cross-presentation and cancer immunity

Giampazolias, Evangelos; Schulz, Oliver; Lim, Kok Haw Jonathan; Rogers, Neil C.; Chakravarty, Probir; Srinivasan, Naren; Gordon, Oliver; Cardoso, Ana; Buck, Michael D.; Poirier, Enzo Z.; Canton, Johnathan; Zelenay, Santiago; Sammicheli, Stefano; Moncaut, Natalia; Varsani-Brown, Sunita; Rosewell, Ian; Sousa, Caetano Reis e

doi:10.1016/j.cell.2021.05.021

Cited by 75 publications

(66 citation statements)

References 72 publications

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“…As a result, data mining identified a subset of those proteins that are associated with the tumor immune responses ( Figure 2A ). Of those proteins, we focused our attention on different proteins, such as gelsolin ( Giampazolias et al, 2021 ), periostin ( Zhou et al, 2015 ; Huizer et al, 2020 ) and osteopontin ( Wei et al, 2019 ; Li et al, 2021 ), which were exclusively detected in the secretome of WT PC + GB, and not in the other conditions. As these proteins might be good markers for GB prognosis dependent on GB-induced CMA in immunosuppressive PC ( Valdor et al, 2019 ), we experimentally confirmed the presence of these proteins and their mouse origin in the secretome of GB-conditioned PC.…”

Section: Resultsmentioning

confidence: 99%

Chaperone-Mediated Autophagy Ablation in Pericytes Reveals New Glioblastoma Prognostic Markers and Efficient Treatment Against Tumor Progression

Molina

García‐Bernal

Salinas

et al. 2022

Front. Cell Dev. Biol.

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Background: The lack of knowledge of the progression mechanisms of glioblastoma (GB), the most aggressive brain tumor, contributes to the absence of successful therapeutic strategies. Our team has recently demonstrated a crucial new role for chaperone-mediated autophagy (CMA) in pericytes (PC)-acquired immunosuppressive function, which prevents anti-tumor immune responses and facilitates GB progression. The possible impact that GB-induced CMA in PC has on other functions that might be useful for future GB prognosis/treatment, has not been explored yet. Thus, we proposed to analyze the contribution of CMA to other GB-induced changes in PC biology and determine if CMA ablation in PC is a key target mechanism for GB treatment.Methods: Studies of RNA-seq and secretome analysis were done in GB-conditioned PC with and without CMA (from knockout mice for LAMP-2A) and compared to control PC. Different therapeutic strategies in a GB mouse model were compared.Results: We found several gene expression pathways enriched in LAMP2A-KO PC and affected by GB-induced CMA in PC that correlate with our previous findings. Phagosome formation, cellular senescence, focal adhesion and the effector function to promote anti-tumor immune responses were the most affected pathways, revealing a transcriptomic profiling of specific target functions useful for future therapies. In addition, several molecules associated with tumor mechanisms and related to tumor immune responses such as gelsolin, periostin, osteopontin, lumican and vitamin D, were identified in the PC secretome dependent on GB-induced CMA. The CMA ablation in PC with GB cells showed an expected immunogenic phenotype able to phagocyte GB cells and a key strategy to develop future therapeutic strategies against GB tumor progression. A novel intravenous therapy using exofucosylated CMA-deficient PC was efficient to make PC reach the tumor niche and facilitate tumor elimination.Conclusion: Our results corroborate previous findings on the impaired immunogenic function of PC with GB-induced CMA, driving to other altered PC functions and the identifications of new target markers related to the tumor immune responses and useful for GB prognosis/therapy. Our work demonstrates CMA ablation in PC as a key target mechanism to develop a successful therapy against GB progression.

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Section: Resultsmentioning

confidence: 99%

Chaperone-Mediated Autophagy Ablation in Pericytes Reveals New Glioblastoma Prognostic Markers and Efficient Treatment Against Tumor Progression

Molina

García‐Bernal

Salinas

et al. 2022

Front. Cell Dev. Biol.

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“…Gelsolin, an abundant actin-depolymerizing plasma protein ( 33 ) decreases binding of F-actin to Clec9a in an in vitro system ( 47 ). In an in vivo cancer model, secreted gelsolin inhibits Clec9a-dependent cross presentation of antigen and dampens CD8+ T cell responses ( 48 ). In this study, we examined the role of gelsolin in neonatal hyperoxia-induced Clec9a+CD103+DC-mediated lung pro-inflammatory responses to RV infection and hypoalveolarization.…”

Section: Discussionmentioning

confidence: 99%

“…Gelsolin depolymerizes F-actin decreasing its binding to Clec9a in an in vitro system ( 47 ). Secreted gelsolin inhibits Clec9a-dependent cross presentation of antigen and dampens CD8+ T cell responses in a cancer model in mice ( 48 ). However, the role of gelsolin in neonatal hyperoxia-induced, Clec9a+CD103+DC-mediated lung pro-inflammatory responses has not been established.…”

Section: Introductionmentioning

confidence: 99%

Gelsolin Attenuates Neonatal Hyperoxia-Induced Inflammatory Responses to Rhinovirus Infection and Preserves Alveolarization

et al. 2022

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Prematurity and bronchopulmonary dysplasia (BPD) increase the risk of asthma later in life. Supplemental oxygen therapy is a risk factor for chronic respiratory symptoms in infants with BPD. Hyperoxia induces cell injury and release of damage-associated molecular patterns (DAMPs). Cytoskeletal filamentous actin (F-actin) is a DAMP which binds Clec9a, a C-type lectin selectively expressed on CD103+ dendritic cells (DCs). Co-stimulation of Clec9a and TLR3 induces maximal proinflammatory responses. We have shown that neonatal hyperoxia (a model of BPD) increases lung IL-12+Clec9a+CD103+ DCs, pro-inflammatory responses and airway hyperreactivity following rhinovirus (RV) infection. CD103+ DCs and Clec9a are required for these responses. Hyperoxia increases F-actin levels in bronchoalveolar lavage fluid (BALF). We hypothesized that the F-actin severing protein gelsolin attenuates neonatal hyperoxia-induced Clec9a+CD103+ DC-dependent pro-inflammatory responses to RV and preserves alveolarization. We exposed neonatal mice to hyperoxia and treated them with gelsolin intranasally. Subsequently we inoculated the mice with RV intranasally. Alternatively, we inoculated normoxic neonatal mice with BALF from hyperoxia-exposed mice (hyperoxic BALF), RV and gelsolin. We analyzed lung gene expression two days after RV infection. For in vitro studies, lung CD11c+ cells were isolated from C57BL/6J or Clec9agfp-/- mice and incubated with hyperoxic BALF and RV. Cells were analyzed by flow cytometry. In neonatal mice, gelsolin blocked hyperoxia-induced Il12p40, TNF-α and IFN-γ mRNA and protein expression in response to RV infection. Similar effects were observed when gelsolin was co-administered with hyperoxic BALF and RV. Gelsolin decreased F-actin levels in hyperoxic BALF in vitro and inhibited hyperoxia-induced D103lo DC expansion and inflammation in vivo. Gelsolin also attenuated hyperoxia-induced hypoalveolarization. Further, incubation of lung CD11c+ cells from WT and Clec9agfp-/- mice with hyperoxic BALF and RV, showed Clec9a is required for maximal hyperoxic BALF and RV induced IL-12 expression in CD103+ DCs. Finally, in tracheal aspirates from mechanically ventilated human preterm infants the F-actin to gelsolin ratio positively correlates with FiO2, and gelsolin levels decrease during the first two weeks of mechanical ventilation. Collectively, our findings demonstrate a promising role for gelsolin, administered by inhalation into the airway to treat RV-induced exacerbations of BPD and prevent chronic lung disease.

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“…Among various DC subsets, cDC1s (XCR1+, CD103+) play a critical role in antitumour immunity. CLEC9A, (also known as DNGR1) is highly expressed on cDC1s and binds necrotic cell debris and promotes antigen processing in tumours (159)(160)(161). One of the reasons for checkpoint blockade failure is poor antigen presentation due to absence of co-stimulatory molecules and therefore modulation of DC function could increase responses to these therapies.…”

Section: Leveraging DC Biology In Cancer Therapiesmentioning

confidence: 99%

Control of Dendritic Cell Function Within the Tumour Microenvironment

2022

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The tumour microenvironment (TME) presents a major block to anti-tumour immune responses and to effective cancer immunotherapy. The inflammatory mediators such as cytokines, chemokines, growth factors and prostaglandins generated in the TME alter the phenotype and function of dendritic cells (DCs) that are critical for a successful adaptive immune response against the growing tumour. In this mini review we discuss how tumour cells and the surrounding stroma modulate DC maturation and trafficking to impact T cell function. Fibroblastic stroma and the associated extracellular matrix around tumours can also provide physical restrictions to infiltrating DCs and other leukocytes. We discuss interactions between the inflammatory TME and infiltrating immune cell function, exploring how the inflammatory TME affects generation of T cell-driven anti-tumour immunity. We discuss the open question of the relative importance of antigen-presentation site; locally within the TME versus tumour-draining lymph nodes. Addressing these questions will potentially increase immune surveillance and enhance anti-tumour immunity.

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Secreted gelsolin inhibits DNGR-1-dependent cross-presentation and cancer immunity

Cited by 75 publications

References 72 publications

Chaperone-Mediated Autophagy Ablation in Pericytes Reveals New Glioblastoma Prognostic Markers and Efficient Treatment Against Tumor Progression

Chaperone-Mediated Autophagy Ablation in Pericytes Reveals New Glioblastoma Prognostic Markers and Efficient Treatment Against Tumor Progression

Gelsolin Attenuates Neonatal Hyperoxia-Induced Inflammatory Responses to Rhinovirus Infection and Preserves Alveolarization

Control of Dendritic Cell Function Within the Tumour Microenvironment

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