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.
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 new Review on extracellular vesicles in cancer is published in Cell Reports.
02/2020. Our new Review on tumour-associated macrophages is published in the Journal of Pathology.
02/2020. Perhaps interested in the phylogeny and taxonomy of Goliathus beetles?
01/2020. Congratulations (again!) to Martina on the acceptance of her 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 available online in Nature Communications.
04/2019. Congratulations to Chiara, Tim and Florent on the acceptance of their paper in Cell Reports!
11/2018. Congratulations to Ioanna and Chiara on the acceptance of their paper 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 now published in Angiogenesis Journal.
05/2018. Our work has been featured in Gen Suisse
11/2017. Congratulations to Mario on the acceptance of his paper 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 RECENT PUBLICATIONS
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 immunotherapy by immune checkpoint blockade, such as 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 drives tumor resistance to immune checkpoint blockade. Disrupting macrophage-Treg interactions with targeted drugs unleashes the efficacy of immune checkpoint blockade, achieving regression of most tumors.
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 could influence the properties of the tumor immune microenvironment.
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 models. Nat 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.
Highlight in Nat Rev Cancer
News&Opinions in The Scientist
Highlights in F1000Prime
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 blockade. Sci 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.
Highlight in ACIR.org
Highlight in Cancer Immunol Res
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.
Keklikoglou, I., Kadioglu, E., Bissinger, S., Langlois, B., Bellotti, A., Orend, G., Ries, C.H., & De Palma, M. Periostin limits tumor response to VEGFA inhibition. Cell 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.
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.
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.
Highlight in Nat Rev Clin Oncol
Highlight in Nat Rev Cancer
Highlight in Nat Rev Drug Discov
News in Cancer Research UK
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 immunity. Nat 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.
News & Views by Lee and Biswas (Nat Cell Biol)
Highlight in Natural History Magazine
Highlight in Biomedical Computation Review