TIM4 expression by dendritic cells mediates uptake of tumor-associated antigens and anti-tumor responses

Caronni, Nicoletta; Piperno, Giulia Maria; Simoncello, Francesca; Romano, Oriana; Vodret, Simone; Yanagihashi, Yuichi; Dress, Regine J.; Dutertre, Charles Antoine; Bugatti, Mattia; Bourdeley, Pierre; Prete, Annalisa Del; Schioppa, Tiziana; Mazza, Emilia Maria Cristina; Collavin, Licio; Zacchigna, Serena; Ostuni, Renato; Vermi, William; Ginhoux, Florent; Bicciato, Silvio; Nagata, Shigekatzu; Benvenuti, Federica

doi:10.1038/s41467-021-22535-z

Cited by 44 publications

(53 citation statements)

References 62 publications

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“…As a possibility, the anti-tumor T cell responses might be activated by PC, through the antigen presentation in response to phagocytosis of immunogenic tumor vesicles or tumor fragments ( Dionisi et al, 2018 ; Li et al, 2018 ; Morris et al, 2018 ). They might also be activated in response to PC phagocytosis of whole tumor cells, which could facilitate the antigen presentation to CD4 + T cells as occurs with some professional antigen-presenting cells ( von Roemeling et al, 2020 ; Caronni et al, 2021 ). In addition, the increased protein expression of some genes associated with the phagosome function ( Supplementary Figure S2 ) also supports the immunogenic phenotype of CMA-deficient PC.…”

Section: Discussionmentioning

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: Discussionmentioning

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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“…However, in our experience (and previously reported by Harusato et al. [1420]) cell yield is greatly reduced when this step is performed. [1416, 1421, 1422] The protocol described here for murine skin processing, can be used for analysis for total skin, or the epidermis and dermis separately. However, each method comes with its own drawbacks.…”

Section: Mononuclear Phagocyte Phenotypesmentioning

confidence: 99%

“…Using a protocol different from the one described here may result in higher expression levels of F4/80 on gut macrophages. Some publications report a heterogeneity of CD11c expression on gut macrophages [1425]. While we chose to focus on the CD11c + population, one may want to consider this when analyzing their data. Tim4 can be a useful marker to be added, for further delineation of macrophage populations [1416]; however, it also has been shown to be expressed on some DC populations [1422]. LCs are the main macrophage population in the epidermis.…”

Section: Mononuclear Phagocyte Phenotypesmentioning

confidence: 99%

Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition)

et al. 2021

Self Cite

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The third edition of Flow Cytometry Guidelines provides the key aspects to consider when performing flow cytometry experiments and includes comprehensive sections describing phenotypes and functional assays of all major human and murine immune cell subsets. Notably, the Guidelines contain helpful tables highlighting phenotypes and key differences between human and murine cells. Another useful feature of this edition is the flow cytometry analysis of clinical samples with examples of flow cytometry applications in the context of autoimmune diseases, cancers as well as acute and chronic infectious diseases. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid. All sections are written and peer-reviewed by leading flow cytometry experts and immunologists, making this edition an essential and state-of-the-art handbook for basic and clinical researchers.

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“…Interestingly, a recent paper by Ruhland et al [35] showed a similar type of formation of cell-cell contacts and synapses between myeloid cells in tumor-draining LNs. Furthermore, a recent study using a murine lung tumor model demonstrated the crucial role of PtdSer receptor TIM-4 in DCs for uptake and cross-presentation of tumor-associated antigens to anti-tumor CD8+ T-cells [36].…”

Section: Discussionmentioning

confidence: 99%

Transfer of Cellular Content from the Allogeneic Cell-Based Cancer Vaccine DCP-001 to Host Dendritic Cells Hinges on Phosphatidylserine and Is Enhanced by CD47 Blockade

Zuo¹,

Lierop²,

Kaspers³

et al. 2021

Cells

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DCP-001 is a cell-based cancer vaccine generated by differentiation and maturation of cells from the human DCOne myeloid leukemic cell line. This results in a vaccine comprising a broad array of endogenous tumor antigens combined with a mature dendritic cell (mDC) costimulatory profile, functioning as a local inflammatory adjuvant when injected into an allogeneic recipient. Intradermal DCP-001 vaccination has been shown to be safe and feasible as a post-remission therapy in acute myeloid leukemia. In the current study, the mode of action of DCP-001 was further characterized by static and dynamic analysis of the interaction between labelled DCP-001 and host antigen-presenting cells (APCs). Direct cell–cell interactions and uptake of DCP-001 cellular content by APCs were shown to depend on DCP-001 cell surface expression of calreticulin and phosphatidylserine, while blockade of CD47 enhanced the process. Injection of DCP-001 in an ex vivo human skin model led to its uptake by activated skin-emigrating DCs. These data suggest that, following intradermal DCP-001 vaccination, local and recruited host APCs capture tumor-associated antigens from the vaccine, become activated and migrate to the draining lymph nodes to subsequently (re)activate tumor-reactive T-cells. The improved uptake of DCP-001 by blocking CD47 rationalizes the possible combination of DCP-001 vaccination with CD47 blocking therapies.

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TIM4 expression by dendritic cells mediates uptake of tumor-associated antigens and anti-tumor responses

Cited by 44 publications

References 62 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

Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition)

Transfer of Cellular Content from the Allogeneic Cell-Based Cancer Vaccine DCP-001 to Host Dendritic Cells Hinges on Phosphatidylserine and Is Enhanced by CD47 Blockade

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