The two overarching themes of my scientific contributions can be summarized as follows:
Intercellular communications play a vital role in tumor-host interactions, and are manifest between stromal cells, such as in the case of endothelial cells and macrophages, and between cancer cells and immune cells. Tumor-host interactions take place both locally – for example to promote angiogenesis at the tumor site; or at distance, via soluble factors and extracellular vesicles, leading to systemic host responses like platelet recruitment or generation of pro-tumoral immunoglobulins.
Immune responses to therapy can restore tumor homeostasis and induce relapse. For instance, bone marrow derived myeloid cells can overcome not only targeted angiogenic blockade, but also promote chemo- and radio-resistance and immunosuppression. On the other hand, macrophage targeted therapies can deplete anti-tumor macrophages (as those present in tumor-draining lymph nodes), triggering alternative pro-tumoral responses, including the generation of pro-tumor immunoglobulins.
The key factor in my research has been a proficient use of lentiviral vector-based genetic engineering techniques that I mastered during my graduate studies in the laboratories of Dr. Luigi Naldini – one of the “fathers” of lentiviral vector technology, and Dr. Michele De Palma, a world leader in the use of lentiviral vectors to study immune cell functions.
During my doctoral work I was interested in the study of Tie2-expressing tumor macrophages and their pro-angiogenic activity because it was emerging that myeloid cells have a major role in tumor relapse after treatment with targeted anti-angiogenic agents. This work identified a pro-angiogenic gene signature (Pucci F. and Venneri MA. et al. Blood 2009) that is being adopted by several other investigators, both in the tumor microenvironment field and in the broader area studying pathological angiogenesis. After developing an inducible knock-down platform (based on Amendola M. et al. Mol Ther 2009), I studied the functional role of the tyrosine kinase receptor Tie2 on tumor macrophages in vivo, and validated it as a novel target for cancer therapy. This work contributed to the development of second-generation anti-angiogenic therapies such as humanized blocking antibodies against Angiopoietin-2 (a Tie2 ligand), which concomitantly prune tumor vessels and disable rebound pro-angiogenic macrophage responses (cover article, Mazzieri R. and Pucci F. et al. Cancer Cell 2011).
During my post-doctoral research, I set out on an ambitious project with the aim of tracking tumor-derived extracellular vesicles (tEVs, nanometer-sized membrane vesicles containing tumor material) in vivo by genetically labeling them with ad-hoc reporters. I was interested in tEVs because numerous reports suggested that they influence the activity of several immune cell types, at least in vitro, but very little was known on the in vivo biology of endogenously released tEVs (Pucci and Pittet Clin Cancer Res 2013). The revealed biodistribution and cellular localization of tEVs led to the serendipitous discovery that lymph node macrophages inhibit tumor growth by limiting tEV-B cell interactions. These interactions, which are induced by tumor progression and certain therapeutic treatments, normally trigger the production of tumor-promoting immunoglobulins (Pucci F et al. Science 2016). These experiments were some of the earliest studies investigating endogenous tEVs, without any in vitro manipulation, and were part of a broader effort to study long range communication between a tumor and distant hemopoietic compartments.
As part of the same effort, I concomitantly developed unbiased approaches to screen for putative endocrine factors mediating tumor-host remote communications. Bio-informatic analysis – merging patient survival and gene expression data with mouse serum proteomics, exposed a candidate circulating factor (PF4, platelet factor 4) associated with worse prognosis in lung cancer patients. In vivo over-expression studies confirmed the presence of a novel link between cancer-induced megakaryocytic expansion in the bone marrow and platelet accumulation at the tumor site, which substantially accelerates Kras-driven lung tumorigenesis (Pucci F. et al. Cell Reports 2016).
Towards the end of my post-doctoral training I was presented with a unique opportunity to work as translational scientist at an early stage biotech company developing a novel T cell-based tumor immunotherapy. The exhaustion of tumor-specific T cells is considered as one of the major factors leading to suppression of anti-cancer immunity. Using novel nano-materials to deliver IL-15, I studied the in vivo pharmacology of tumor-antigen primed human T cells (Abstract 3577, AACR 2018) and patented the use of nano-formulated IL-15 to sustain the viability of T cell therapy products during freeze-thaw cycles (U.S. Patent Application Serial No. 62/349473).Read more
Areas of interest
- Tumor immunology
- Humoral immunity
- Lymph node biology
- Cellular senescence
- Extracellular vesicle biology
- Therapeutic cancer vaccines
- Ph.D., San Raffaele University, Milan Italy 2010
- European Molecular Biology Organization – Long-Term fellowship
- Italian Association for Cancer Research – Post-doctoral Fellowship
- Massachusetts General Hospital – Post-doctoral Fellowship
Honors and awards
- V Foundation Scholar
- OHSU-CRUK early detection award
Memberships and associations
- American Association for Cancer Research
Pucci, F.; Garris, C.; Lai, C. P.; Newton, A.; Pfirschke, C.; Engblom, C.; Alvarez, D.; Sprachman, M.; Evavold, C.; Magnuson, A.; von Andrian, U. H.; Glatz, K.; Breakefield, X. O.; Mempel, T. R.; Weissleder, R.; Pittet, M. J. SCS macrophages suppress melanoma by restricting tumor-derived vesicle-B cell interactions. Science 352:242-246; 2016. PMID: 26989197. F1000 recommended article
- "FcRÎ³ Activation Regulates Inflammation-Associated Squamous Carcinogenesis" Cancer Cell February 17 2010
- "Immunogenic Chemotherapy Sensitizes Tumors to Checkpoint Blockade Therapy" Immunity February 16 2016
- "Identification of proangiogenic TIE2-expressing monocytes (TEMs) in human peripheral blood and cancer" Blood June 15 2007
- "SCS macrophages suppress melanoma by restricting tumor-derived vesicle-B cell interactions" Science April 8 2016
- "Tle1 tumor suppressor negatively regulates inflammation in vivo and modulates NF-ÎºB inflammatory pathway" Proceedings of the National Academy of Sciences of the United States of America February 16 2016
- "Tumor-Targeted Interferon-Î± Delivery by Tie2-Expressing Monocytes Inhibits Tumor Growth and Metastasis" Cancer Cell October 7 2008
- "PHD2 regulates arteriogenic macrophages through TIE2 signalling" EMBO Molecular Medicine June 1 2013
- "Bimodal CD40/Fas-Dependent Crosstalk between iNKT Cells and Tumor-Associated Macrophages Impairs Prostate Cancer Progression" Cell Reports March 13 2018
- "TIE2-expressing macrophages limit the therapeutic efficacy of the vascular-disrupting agent combretastatin A4 phosphate in mice" Journal of Clinical Investigation May 2 2011
- "MiR-511-3p Modulates Genetic Programs of Tumor-Associated Macrophages" Cell Reports February 23 2012
- "A distinguishing gene signature shared by tumor-infiltrating Tie2-expressing monocytes, blood "resident" monocytes, and embryonic macrophages suggests common functions and developmental relationships" Blood November 19 2009
- "PF4 Promotes Platelet Production and Lung Cancer Growth" Cell Reports November 8 2016
- "Regulated and multiple miRNA and siRNA delivery into primary cells by a lentiviral platform" Molecular Therapy March 18 2009
- "Angiotensin II Drives the Production of Tumor-Promoting Macrophages" Immunity February 21 2013
- "Transplanted neural stem/precursor cells instruct phagocytes and reduce secondary tissue damage in the injured spinal cord" Brain January 1 2012
- "Targeting the ANG2/TIE2 Axis Inhibits Tumor Growth and Metastasis by Impairing Angiogenesis and Disabling Rebounds of Proangiogenic Myeloid Cells" Cancer Cell April 12 2011
- " Osteoblasts remotely supply lung tumors with cancer-promoting SiglecF high neutrophils " Science December 1 2017
- "Molecular pathways" Clinical Cancer Research May 15 2013
- "A role for miR-155 in enabling tumor-infiltrating innate immune cells to mount effective antitumor responses in mice" Blood January 1 2013