Principal Investigator/s: Prof. Andrea Balsari (Full Professor) / Dr. Lucia Sfondrini (Research Assistant Professor)

 

Collaborators: Dr. Michele Sommariva (Italian Government Fellowship for Scientific Research and Training),  Dr. Valentina Uva (PhD student),  Dr. Alessandra Cataldo (PhD student), Dr. Alessandra Meini (PhD student), Dr. Valentino Le Noci (collaborator)

 

The group’s research activity is focused on:

Currently, the research has its primary focus on three  major research lines:

Topic 1. Antitumor activity of locoregional administration of CpG-ODN. Toll-like receptors (TLRs) recognize a set of conserved pathogen-associated molecular patterns, which allows them to sense pathogens and initiate immune response. TLR agonists represent a novel approach to stimulate an effective antitumor response, because they are unique in their ability to stimulate both innate and adaptive immune response. TLR9, which is expressed on cells of the immune system and on endothelial cells, fibroblast and epithelial cells, recognizes and is activated by unmethylated cytosinephosphate-guanine (CpG) dinucleotides. We previously observed a significant antitumor effect in mice bearing advanced-stage human ovarian carcinomas when CpGODN was delivered intraperitoneally, but not when administered subcutaneously or intravenously, and using a daily instead of a weekly intraperitoneal CpG-ODN delivery schedule, suggesting a relevant role for local activation of cells and cytokines of innate immunity in the antitumor therapeutic effect of this agent. However, since daily i.p. administration of CpG-ODN induced a significant increase of survival-time but no cure a single mouse, aim of this project is to evaluate in different xenograft human ovarian cancer models if combination of local and repeated CpG-ODN administration with other antitumor therapies can increase benefits observed with targeted immunotherapy alone. In particular, we will evaluate the effectiveness of CpG-ODN in combination with monoclonal antibody directed against components expressed in ovarian cancer, cytotoxic chemotherapeutic  drugs and other TLR agonists (Poly(I):Poly(C)). For those therapeutic combinations which result more efficacy than treatment with CpG-ODN alone, further studies will be performed to elucidate the mechanism underlie the additive or synergistic effect and to accurately monitor the contribution of immune and non-immune effectors. Moreover, we are actually evaluating a possible loco-regional therapy with CpG-ODN administered by aerosol to treat lung tumor or metastases.

 

Topic 2. Role of FoxP3 expression on metastatic process in breast cancer. Forkhead box P3 (FOXP3), a member of the forkhead/winged-helix family of transcription genes implicated in regulating immune system development and function, is expressed in cells of multiple lineages. The majority of studies conducted in samples from human cancer patients, including our analyses in breast carcinomas, indicate that FOXP3 expression correlates with poor prognosis, especially with distant metastasis. The overall goal of this project is to identify molecules potentially relevant for FOXP3-driven metastasis in breast carcinoma cells. Specifically, we are analyzing in experimental models the ability of FoxP3 to induce metastatic process by modulating molecules involved in migration, invasive capacity and/or inhibition of the immune response. The molecules modulated by FoxP3 resulted relevant in this process will be then validated in series of human primary breast carcinoma specimens and their expression correlated with tumor progression. The discovery of genes and/or cellular functions regulated by FOXP3 in tumor cells promises to provide not only the rational explanation for the involvement of this transcription factor in tumor invasion, but also new molecular targets for improving therapeutic strategies.

 

Role of PD-1 molecule in anti-tumor innate immune response. A strategy by which tumors evade an immune response involves induction of reduced immune cell functional capacity through their expression of agonists recognized by inhibitory receptors on the immune cell surface. Some of these inhibitory receptors, such as Programmed Death-1 (PD-1), are expressed on both adaptive and innate immune cells. Thus, blocking these receptors on innate immune effector cells could increase the antitumor activity of a local therapy with TLR agonists. Our study will determine whether the antitumor effects of locally and repeatedly administered TLR9 agonists increase when CpG-ODN is combined to antibodies that block PD-1.

 

Recent/relevant publications

Sfondrini,L., Sommariva,M., Tortoreto,M., Meini,A., Piconese,S., Calvaruso,M., Van,R.N., Bonecchi,R., Zaffaroni,N., Colombo,M.P., Tagliabue,E., and Balsari,A. Anti-tumor activity of CpG-ODN aerosol in mouse lung metastases. Int J Cancer (2013) [Epub ahead of print].

Sommariva,M., De Cesare,M., Meini,A., Cataldo,A., Zaffaroni,N., Tagliabue,E., and Balsari,A. High efficacy of CpG-ODN, Cetuximab and Cisplatin combination for very advanced ovarian xenograft tumors. J Transl Med 29: 11:25 (2013).

Rossini A, Giussani M, Giacomini A, Guarnotta C, Tagliabue E, Balsari A. “Surveillance of spontaneous breast cancer metastasis by TRAIL-expressing CD34⁺ cells in a xenograft model.” Breast Cancer Res Treat 136:457-67 (2012).

Sommariva,M., De Cecco,L., De Cesare,M., Sfondrini,L., Ménard,S., Melani,C., Delia,D., Zaffaroni,N., Pratesi,G., Uva,V., Tagliabue,E., and Balsari,A. TLR9-agonists oppositely modulate DNA-repair genes in tumor vesus immune cells and ehance chemotherapy effects. Cancer Res, 71:6382-6390 (2011).

Merlo A, Casalini P, Carcangiu ML, Malventano C, Triulzi T, Ménard S, Tagliabue E, Balsari A. FOXP3 expression in breast tumors and overall patient survival. J Clin Oncol 27:1746-52 (2009).

 

Contacts

Prof:  Andrea Balsari tel. 02-23902564, email andrea.balsari@unimi.it

Dott. Lucia Sfondrini  tel. 02-23903780  email lucia.sfondrini@unimi.it