Research interests
Our lab has contributed to elucidating the heterogeneity of macrophages in mouse models of cancer. We identified and characterized a subpopulation of tumor-associated macrophgages (TAMs) with monocyte origin that associates with tumor blood vessels and sustains angiogenesis in mouse and human cancer. We have also characterized VEGFA-independent modes of tumor angiogenesis, and illustrated the therapeutic opportunities afforded by inhibiting angiopoietin 2 (ANGP2/ANG2) signaling in de novo models of metastatic cancer. More recently, we presented pre-clinical evidence for the efficacy of “anti-angiogenic immunotherapy” in mouse cancer models.
Currently, we employ genetic cancer models and cell-engineering strategies, largely based on lentiviral gene transfer, to dissect and reprogram the interactions between blood vessels and immune cells in tumors, primarily by focusing on angiogenic signaling, microRNA regulation, and secreted extracellular vesicles. 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:
- Engineered dendritic cell vaccines for cancer immunotherapy;
- Targeting or reprogramming tumor-associated macrophages;
- Anti-angiogenesis as a tumor-conditioning strategy for improving cancer immunotherapy;
- Tumor-derived extracellular vesicles.
Growth and metastasis of malignant tumors depend on angiogenesis, the formation of tumor-associated blood vessels. Tumor angiogenesis is intimately interconnected with immunomodulatory networks that are orchestrated by tumor-infiltrating leukocytes, including macrophages and regulatory T cells (T-regs). We have shown that optimized regimens of anti-angiogenic drugs can reprogram the tumor-associated vasculature to a form that facilitates the deployment and efficacy of standard-of-care immune therapies. However, tumors can develop adaptation/evasion mechanisms that limit the efficacy of “anti-angiogenic immunotherapy”, and combination with other classes of anticancer drugs is required to improve therapeutic responses.
Some key papers and reviews:
Martinez-Usatorre A*, Kadioglu E*, Boivin G, […], Ries CH, Meylan E, & De Palma M. Overcoming microenvironmental resistance to PD-1 blockade in genetically engineered lung cancer models. Sci Transl Med. 2021 Aug 11;13(606):eabd1616.
Kashyap, A.S.*, Schmittnaegel, M.*, Rigamonti, N., […], Corse, E., & De Palma, M.*, Zippelius, A*. Optimized anti-angiogenic reprogramming of tumor microenvironment by VEGFA and angiopoietin-2 blockade potentiates CD40 immunotherapy. Proc. Natl. Acad. Sci. U.S.A. 2020 .
Ragusa, S., Prat-Luri, B., González-Loyola, A., […], Delorenzi, M., De Palma, M., & Petrova, T.V. Anti-angiogenic immunotherapy suppresses desmoplastic and chemoresistant intestinal tumors in mice. J Clin Invest., 2020 Mar 2;130(3):1199-1216.
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, […], 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.
Tumor-associated macrophages (TAMs) are critical inflammatory cell components of tumors. They regulate several key processes in tumors, such as 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. Interfering with TAM’s immunosuppressive and pro-tumoral functions may provide opportunities for improving the efficacy of frontline cancer immunotherapies.
Some key papers and reviews:
Martinez-Usatorre, A.*, Kadioglu, E.*, Boivin, G., […], 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 Aug 11;13(606):eabd1616.
Beltraminelli, T. & De Palma, M. Biology and therapeutic targeting of tumor-associated macrophages. J Pathol. 2020 Apr;250(5):573-592.
Neubert N J*, Schmittnaegel M*, Bordry N*, […], 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.
Recent studies have shown that tumor-derived extracellular vesicles, such as 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 anti-cancer therapies. We further explore the potential of tumor-derived extracellular vesicles as nanocarries of tumor antigens for repurposing dendritic cell cancer vaccines.
Some key papers and reviews:
Beltraminelli, T., Perez, C.R. & De Palma, M. Disentangling the complexity of tumor-derived extracellular vesicles. Cell Rep. 2021 Apr 6;35(1):108960.
Cianciaruso, C.*, Beltraminelli, T.*, Duval, F.*, […], 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., […], 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.
Squadrito ML, Cianciaruso C, Hansen SK, & De Palma M. EVIR: chimeric receptors that enhance dendritic cell cross-dressing with tumor antigens. Nat Methods. 2018 Mar;15(3):183-186.
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.