Abstract
Pancreatic Ductal Adenocarcinoma (PDA) is an almost incurable radio- and chemo-resistant tumor, and its microenvironment is characterized by a strong desmoplastic reaction associated with a significant infiltration of T regulatory lymphocytes and myeloid-derived suppressor cells (Tregs, MDSC). Investigating immunological targets has identified a number of metabolic and cytoskeletal related molecules, which are typically recognized by circulating antibodies. Among these molecules we have investigated alpha-enolase (ENO1), a glycolytic enzyme that also acts a plasminogen receptor. ENO1 is also recognized by T cells in PDA patients, so we developed a DNA vaccine that targets ENO1. This efficiently induces many immunological processes (antibody formation and complement-dependent cytotoxicity (CDC)-mediated tumor killing, infiltration of effector T cells, reduction of infiltration of myeloid and Treg suppressor cells), which significantly increase the survival of genetically engineered mice that spontaneously develop pancreatic cancer. Although promising, the ENO1 DNA vaccine does not completely eradicate the tumor, which, after an initial growth inhibition, returns to proliferate again, especially when Tregs and MDSC ensue in the tumor mass. This led us to develop possible strategies for combinatorial treatments aimed to broaden and sustain the antitumor immune response elicited by DNA vaccination. Based on the data we have obtained in recent years, this review will discuss the biological bases of possible combinatorial treatments (chemotherapy, PI3K inhibitors, tumor-associated macrophages, ENO1 inhibitors) that could be effective in amplifying the response induced by the immune vaccination in PDA.
Highlights
The crucial role of anti-ENO1 antibodies was confirmed by the observation that ENO1 mice showed B cells organized in dense aggregates that displayed a distinct structure, the so-called vaccinated mice showed B cells organized in dense aggregates that displayed a distinct structure, the tertiary lymphoid tissue (TLT), which were not found in normal pancreases, and only sporadically so-called tertiary lymphoid tissue (TLT), which were not found in normal pancreases, and only in Pancreatic Ductal Adenocarcinoma (PDA) of untreated mice or those vaccinated with an empty-vector [21]
This approach has been confirmed in preclinical studies in which we have observed that the combination of CTX and ENO1 vaccination in genetically engineered mouse models (GEM) mice was much more efficacious in inducing anti-ENO1 antibodies that ENO1 vaccination alone [38]
Having established that immunological targeting of ENO1 by DNA vaccination is a powerful stimulus for humoral and cellular responses against PDA (Figures 1 and 4), the generation of immunotherapy will take advantage of recent data on the effects of chemotherapy to extend and amplify the immune response against ENO1 and predispose the immune system to promptly respond to ENO1 and other TAAs, as well as data demonstrating the effectiveness of the inhibition of Phosphoinositide 3-Kinase (PI3K)
Summary
Great efforts have been invested in developing approaches for eliciting anti-tumor responses by priming a novel (or boosting an existing) immune response against tumor cells These have included different strategies from antibodies to vaccines, and the huge amount of pre-clinical and clinical results have led to the approval of some of these treatments by the U.S. Food and Drug Administration agency and the European Medicines Agency, as immunotherapy for cancer patients. Th1/Th17 (IFNγ and/or IL17 producers) phenotype in the marginal tumor area paralleled by a higher number of clones with a T regulatory lymphocytes (Treg) phenotype (FoxP3+ and IL10 producers) [14] These results suggested the presence of antigen-specific T cells into the tumor that, are frustrated in their functions by the presence of Tregs.
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