Our lab has contributed to elucidating the pro-angiogenic functions of monocytes/macrophages in mouse models of cancer, as well as the molecular and functional heterogeneity of macrophages in both experimental and human tumors. We have also characterized VEGFA-independent modes of tumor angiogenesis, and illustrated the therapeutic opportunities afforded by inhibiting angiopoietin signaling in de novo models of metastatic cancer. Currently, we employ genetic cancer models and cell-engineering strategies, largely based on lentiviral gene transfer, to dissect the interactions between macrophages, blood vessels and T cells in tumors, primarily by focusing on angiogenic signaling, immune checkpoints, microRNA regulation, and secreted exosomes. By tackling these processes, we aim to reprogram the immunosuppressive tumor microenvironment to a form that enhances the efficacy of anticancer therapies and facilitates the deployment of anti-tumor immunity.
Current research interests include:
- Molecular and functional heterogeneity of tumor-associated macrophages;
- microRNA regulation of macrophage functions in tumors;
- Anti-angiogenesis as a tumor-conditioning strategy for improving cancer immunotherapy;
- Mechanisms of tumor resistance to anti-angiogenic therapy;
- Tumor-derived exosomes;
- Engineered dendritic cell vaccines for cancer immunotherapy.
Targeting angiogenesis and immunosuppression in tumor models
Growth and metastasis of malignant tumors depend on angiogenesis, the formation of tumor-associated blood vessels. Accumulating evidence indicates that tumor angiogenesis is intimately interconnected with immunomodulatory networks that are orchestrated by tumor-infiltrating leukocytes, including macrophages. The angiopoietin (ANGPT) receptor, TIE2, is expressed by the endothelial cells of blood vessels and a subpopulation of perivascular macrophages with immunosuppressive functions (TIE2-expressing macrophages, TEMs). We have recently reported that the combined blockade of VEGFA and ANGPT2 signaling inhibits tumor angiogenesis and metastasis in some GEMMs of cancer by reprogramming both the blood vessels and the immune microenvironment. However, tumors can develop adaptation/evasion mechanisms that limit the efficacy of angiogenesis inhibition, and combination with other classes of anticancer drugs is required to improve therapeutic responses. To this aim, we combine angiogenesis inhibitors with strategies that target or reprogram the immunosuppressive tumor microenvironment. Approaches include tumor-associated macrophage (TAM) depletion or reprogramming, immune-checkpoint blockade, and other immunostimulatory strategies.
Recent key papers:
Keklikoglou I, Kadioglu E, Bissinger S, Langlois B, Bellotti A, Orend G, Ries CH, & De Palma M. Periostin limits tumor response to VEGFA inhibition. Cell Rep. 2018 Mar;22(10):2530-2540.
Schmittnaegel M, & De Palma M. Reprogramming tumor blood vessels for enhancing immunotherapy. Trends Cancer. 2017 Dec 3(12):809-812.
De Palma M, Biziato D, & Petrova TV. Microenvironmental regulation of tumor angiogenesis. Nat Rev Cancer. 2017 Aug 17(8):457-474.
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.
Rigamonti N*, Kadioglu E*, Keklikoglou I, Wyser Rmili C, Leow CC, & De Palma M. Role of angiopoietin-2 in adaptive tumor resistance to VEGF signalling blockade. Cell Rep. 2014 Aug 7;8(3):696-706.
Mazzieri R*, Pucci F*, Moi D, Zonari E, Ranghetti A, Berti A, Politi LS, Gentner B, Brown J, Naldini L*, & De Palma M*. Targeting the ANG2/TIE2 axis inhibits tumor growth and metastasis by impairing angiogenesis and disabling rebounds of proangiogenic myeloid cells. Cancer Cell. 2011 Apr 12;19(4):512-26.
Targeting or reprogramming tumor-associated macrophages
Tumor-associated macrophages (TAMs) are critical inflammatory cell components of tumors. They regulate several key processes in tumors, most notably angiogenesis, matrix remodeling and immunity, and exert both protumoral and antitumoral functions depending on their activation and phenotype. Increasing data indicate that TAMs can be programmed to acquire immunostimulatory functions in tumors. We have shown that this can be achieved, for example, by modulating their expression of certain microRNAs (miRNAs) — a class of non-coding RNAs that regulate gene expression at the posttranscriptional level. Suppressing Let-7 activity in TAMs promoted their acquisition of immunostimulatory functions, which synergized with cancer immunotherapies such as PD1 checkpoint blockade and CD40 agonistic antibodies. Interfering with TAM’s immunosuppressive and pro-tumoral functions may provide opportunities for improving the efficacy of frontline cancer immunotherapies.
Recent key papers:
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.
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.
De Palma M, & Lewis C E. Macrophage regulation of tumor responses to anticancer therapies. Cancer Cell. 2013 Mar 18; 23(3):277-286.
Squadrito ML, Pucci F, Magri L, Moi D, Gilfillan DG, Ranghetti A, Casazza A, Mazzone M, Lyle R, Naldini L, & De Palma M. miR-511-3p modulates genetic programs of tumor-associated macrophages. Cell Rep. 2012 Feb 23;1(2):141-154.
Harnessing tumor-derived extracellular vesicles
Recent studies have shown that tumor-derived extracellular vesicles (including exosomes) influence tumor progression and metastasis. Interestingly, both cancerous and associated stromal cells – including TAMs – release extracellular vesicles that contain microRNAs and other functional macromolecules. We are currently studying the significance of tumor-derived extracellular vesicles for tumor angiogenesis, metastasis, and response to anticancer therapies. We further explore the potential of tumor-derived extracellular vesicles as nanocarries of tumor antigens for repurposing dendritic cell cancer vaccines.
Recent key papers:
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.
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. 2018 Dec 31 Epub.
Squadrito ML, Cianciaruso C, Hansen SK, & De Palma M. EVIR: chimeric receptors that enhance dendritic cell cross-dressing with tumor antigens. Nat Methods. 2018 Jan 22.
Squadrito ML*, Baer C*, Burdet F, Maderna C, Gilfillan GD, Lyle R, Ibberson M, & De Palma M. Endogenous RNAs modulate microRNA sorting to exosomes and transfer to acceptor cells. Cell Rep. 2014;11;8(5):1432-1446.