Targeting The Stroma To Hit The Tumor: Mmp11 As A Novel Target For Cancer Immunotherapy

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PAMatrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that mediate a number of physiological and pathological processes, such as matrix degradation, tissue remodeling, inflammation and tumor metastasis. The objective of this study was to develop and characterize a vaccine targeting stromal antigens expressed by cancer associated fibroblasts (CAFs). We focused on MMP11 (or stromelysin 3, ST3), that has been detected primarily in CAFs and its expression correlates with aggressive clinical behavior and invasiveness of different types of carcinoma. We demonstrated that intramuscular injection of genetic vectors such as Adenovirus (Ad) and plasmid DNA encoding MMP11 engineered variants followed by in vivo electroporation (DNA-EP) resulted in breakage of immune tolerance and induction of both cell mediated and humoral immune response. Importantly, MMP11 vaccine was able to confer significant antitumoral protection in a chemically induced, MMP11 overexpressing colon cancer model both in prophylactic and therapeutic settings. To determine the mechanism of action of MMP11 vaccine, we have utilized IFNgamma- and μmicroMT-knock out mice, devoid of T- and B-cell immune response, respectively. Our results show that both arms of the immune response are important to confer the therapeutic effect. Moreover, MMP11 stromal vaccine showed synergic effects when combined with genetic vaccines targeting classic tumor associated antigens, such as telomerase reverse transcriptase (TERT) and carcinoembryonic antigen (CEA). Finally, to assess the immunogenicity and the safety of MMP11 vaccine in a large animal model, nonhuman primates have been vaccinated with Ad and DNA-EP. A strong immune response was measured with no detectable side effects. In addition, MMP11 detection and spontaneous immune responses in the blood of breast and prostate cancer patients further corroborate MMP11 as a valid target for immune intervention.Taken together, these data support the use of MMP11 as a potential candidate for cancer immunotherapy in human clinical trials.Citation Format: Laura Luberto, Rita Mancini, Arianna Di Napoli, Daniela Peruzzi, Federica Mori, Giuseppe Roscilli, Emanuele Marra, Manuela Cappelletti, Gennaro Ciliberto, Luigi Aurisicchio. Targeting the stroma to hit the tumor: MMP11 as a novel target for cancer immunotherapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 291. doi:10.1158/1538-7445.AM2015-291