De Palma lab

Angiogenesis and Tumor Microenvironment

Our laboratory investigates the interactions between genetically altered cancer cells and the ostensibly normal host tissues in which tumors arise, progress and develop to metastatic disease. We focus on the cross talk between malignant cells and the vascular system, immune cells, and secreted extracellular vesicles (exosomes), and the mechanisms whereby these heterotypic interactions regulate tumor progression in experimental cancer models. This is being studied primarily in genetic models of breast and lung cancer, and melanoma, in which both malignant and host cells are engineered to be visualized or depleted, or to modify their expression of genes of interest. Furthermore, we examine how the interplay between the tumor and the host can be harnessed for improving tumor response to anti-cancer therapies, in particular immunotherapies.



NEWS


11/2023. Congratulations to Ali and all collaborators on the publication of our study on engineered dendritic cell progenitors, which is online in Nature Cancer.

08/2021. Congratulations to Amaia and Ece on the publication of their study on immunotherapy resistance in lung cancer, which is out now in Science Translational Medicine.

04/2021. Our Review on extracellular vesicles in cancer is published in Cell Reports.

02/2020. Our Review on tumour-associated macrophages is published in the Journal of Pathology.

02/2020. Perhaps interested in the phylogeny and taxonomy of Goliathus beetles?

02/2020. Initial results of our collaboration with Tanya Petrova‘s group just published in the Journal of Clinical InvestigationAnti-angiogenic immunotherapy for chemoresistant colorectal cancer.

01/2020. Congratulations to Martina on the acceptance of her “anti-angiogenic immunotherapy” paper in PNAS, a study in collaboration with the Zippelius lab in Basel.

11/2019. Our Review on engineered dendritic cell vaccines for cancer immunotherapy is published in Nature Communications

04/2019. Congratulations to Chiara, Tim and Florent on the publication of their paper on macrophage-derived exosomes, now online in Cell Reports

01/2019. Congratulations to Ioanna and Chiara for their study on chemotherapy-induced, pro-metastatic exosomes, published in Nature Cell Biology

08/2018. Welcome back, Caleb

08/2018. Our review article on perivascular macrophages has been published in Nature Reviews Immunology.

05/2018. The review article “Consensus guidelines for the use and interpretation of angiogenesis assays” is published in Angiogenesis Journal.

05/2018. Our work has been featured in Gen Suisse

04/2018. Congratulations to Ioanna and Martina on the publication of their papers in Cell Reports and Science Translational Medicine

11/2017. Miki is the 2017 recipient of the Robert Wenner Prize (for Italian click here) for cancer research, awarded by the Swiss Cancer League.

01/2018. Congratulations to Mario on the publication of his paper on dendritic cell engineering in Nature Methods!

08/2017. Want to know more of how the tumor microenvironment regulates angiogenesis

12/2016. Miki has been awarded an ERC consolidator grant (CoG). The project will develop a new generation of cancer vaccines based on engineered dendritic cells.



SELECTED PUBLICATIONS

Ghasemi A, Martinez-Usatorre A, Li L, […], Migliorini D, Heikenwalder M, & De Palma M. Cytokine-armed dendritic cell progenitors for antigen-agnostic cancer immunotherapy. Nat Cancer. 2023; 10.1038/s43018-023-00668-y.

Key findings: We describe a population of laboratory-engineered dendritic cell progenitors (DCPs) that suppress tumor growth by activating anti-tumor immunity without the need for ex vivo antigen loading. These cytokine-armed DCPs are effective in various cancer models and synergize with CAR-T cells in eradicating gliomas in mice.

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Research briefing in Nature Cancer

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Martinez-Usatorre, A.*, Kadioglu, E.*, Boivin, G., Cianciaruso, C., Guichard, A., Torchia, B., Zangger, N., Nassiri, S., Keklikoglou, I., Schmittnaegel., M., Ries, C.H., Meylan, E., & De Palma, M. Overcoming microenvironmental resistance to PD-1 blockade in genetically engineered lung cancer models. Sci Transl Med. 2021; (13)eabd1616.

Key findings: Most lung cancers are resistant to immune checkpoint blockade (ICB) with PD-1 or PD-L1 antibodies, also in combination with front-line drugs. Using genetically engineered mouse models of lung cancer, we identify a therapy-induced cross talk between macrophages and regulatory T cells (Tregs) that sustains tumor resistance to ICB. Disrupting macrophage-Treg interactions with targeted drugs unleashes the efficacy of ICB, achieving regression of most tumors.

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Cianciaruso, C.*, Beltraminelli, T.*, Duval, F.*, Nassiri, S., Hamelin, R., Mozes, A., Gallart-Ayala, H., Ceada Torres, G., Torchia, B., Ries, C.H., Ivanisevic, J., & De Palma, M. Molecular profiling and functional analysis of macrophage-derived tumor extracellular vesicles. Cell Rep. 2019 June 4;27(10):3062-3080.e11.

Key findings: We develop methods for the analysis of extracellular vesicles secreted by tumor-associated macrophages (TAM-EVs). Proteomic and lipidomic profiling indicates that TAM-EVs carry modulators of inflammation and lipid metabolism that may influence the properties of the tumor immune microenvironment.

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Keklikoglou, I.*, Cianciaruso, C.*, Güç, E., Squadrito, M.L., Spring, L.M., Tazzyman, S., Lambein, L., Poissonnier, A., Ferraro, G.B., Baer, C., Cassará, A., Guichard, A., Iruela-Arispe, M.L., Lewis, C.E., Coussens, L.M., Bardia, A., Jain, R.K., Pollard, J.W., & De Palma, M. Chemotherapy elicits pro-metastatic extracellular vesicles in breast cancer modelsNat Cell Biol. 2019 Feb;21(2):190-202.

Key findings: We show that two classes of chemotherapeutic agents elicit mammary tumor-derived extracellular vesicles that facilitate the establishment of pulmonary metastasis. This process involves chemotherapy-mediated effects on the protein composition of the extracellular vesicles and their ability to activate a pro-inflammatory and metastasis-supportive response in the lung endothelium.

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Neubert, N. J.*, Schmittnaegel, M.*, Bordry, N.*, Nassiri, S., Wald, N., Martignier, C., Tillé, L., Hemicsko, K., Damsky, W., Maby El-Hajjami, H., Klaman, I., Danenberg, E., Ioannidou, K., Kandalaft, L., Coukos, G., Hoves, S., Ries, C. H., Fuertes Marraco, S. A., Foukas, P. G., & De Palma, M.§, Speiser, D.E.§ T cell-induced CSF1 promotes melanoma resistance to PD1 blockadeSci Transl Med. 2018 Apr 11;10(436), pii: eaan3311.

Key findings: We show that activated T cells elicit an immunosuppressive response in melanoma that involves the induction of CSF1 and the recruitment of macrophages. High infiltration of both T cells and macrophages in human melanoma associates with poor response to PD1 immune checkpoint blockade. Elimination of macrophages unleashes the therapeutic potential of PD1 blockade in experimental melanoma models.

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Squadrito, M.L., Cianciaruso, C., Hansen, S.K., & De Palma, M. EVIR: chimeric receptors that enhance dendritic cell cross-dressing with tumor antigens. Nat Methods. 2018 Mar;15(3):183-186.

Key findings: In this article we describe a new chimeric receptor, termed EVIR, with endows dendritic cells with the ability to uptake extracellular vesicles released from the patient’s own tumor and to present pre-formed MHCI/tumor antigens to the immune system, without manipulation of tumor antigens ex vivo. EVIR-engineered dendritic cells may represent a new class of tumor vaccine for personalized therapeutic applications.

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Keklikoglou, I., Kadioglu, E., Bissinger, S., Langlois, B., Bellotti, A., Orend, G., Ries, C.H., & De Palma, M. Periostin limits tumor response to VEGFA inhibitionCell Rep. 2018 Mar;22(10):2530-2540.

Key findings: We show that tumor resistance to VEGFA inhibition (a clinically approved anti-angiogenic treatment) is dependent on periostin, a matricellular protein expressed by stromal cells. Periostin orchestrates VEGFA-independent tumor angiogenesis, in part, by recruiting pro-angiogenic macrophages.

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De Palma, M., Biziato, D., & Petrova, T.V. Microenvironmental regulation of tumour angiogenesis. Nat Rev Cancer. 2017 Aug;17(8):457-474.

Key findings: A review that illustrates the complex regulation of angiogenesis by the tumor microenvironment.

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Schmittnaegel, M.*, Rigamonti, N.*, Kadioglu, E., Cassará, A., Wyser Rmili, C., Kiialainen, A., Kienast, Y., Mueller, H.-J., Ooi, C.-H., Laoui, D., & De Palma, M. Dual angiopoietin-2 and VEGFA inhibition elicits antitumor immunity that is enhanced by PD-1 checkpoint blockade. Sci Transl Med. 2017 Apr 12;9(385), pii: eaak9670.

Key findings: This study shows that optimized regimens of anti-angiogenic drugs targeting angiopoietin-2 and VEGFA elicit anti-tumor immunity in experimental cancer models. This involves effects on both the tumor blood vessels and intra-tumoral phagocytes, which fosters cytotoxic T cell activation and extravasation to the tumors. Concurrently, the therapeutic benefits are tempered by the adaptive induction of the immune checkpoint ligand PDL1 in vascular endothelial cells, which can be overcome through pharmacological PD1 inhibition.

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Baer C*, Squadrito ML*, Laoui D, Thompson D, Hansen SK, Kiialainen A, Hoves S, Ries CH, Ooi C-H, & De Palma M. Suppression of microRNA activity amplifies IFN-γ-induced macrophage activation and promotes anti-tumor immunityNat Cell Biol. 2016 Jul;18(7):790-802.

Key findings: This study shows that suppressing microRNA activity in tumor-associated macrophages (TAMs) abates their immunosuppressive functions and prompts recruitment and activation of T cells in the tumors. TAM reprogramming enabled tumor eradication by PD1 checkpoint blockade or CD40 agonistic antibodies. These findings indicate that microRNA activity opposes immunostimulatory TAM activation, with potential therapeutic implications.

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News & Views by Lee and Biswas (Nat Cell Biol)

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