Tumor Immunology Lab

The Tumor Immunology Lab aims at the identification of novel therapeutic strategies for the treatment of a very dismal cancer such as the pancreatic ductal adenocarcinoma (PDAC). Dr Novelli and Dr Cappello have been studying the immune response in PDAC patients for twenty years, and Dr Curcio joined the group as an expert in anti-tumor vaccine eight years ago. Our goal, indeed, is the development of immunotherapeutic strategies based on the use of a DNA vaccine that codes for molecules selected among those that when expressed by the cancer cells induced a strong antibody and cellular reaction in PDAC patients. For this each PI is focused on different aspects: 

i) identification of molecular targets to promote an antitumor immune response (Dr Novelli); ii) development of DNA vaccines, to set up and implement clinical protocols for pancreatic cancer immunotherapy (Dr Curcio); 

iii) characterization of tumor microenvironment before or after different immunotherapy (Dr Cappello).

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in Western countries, and it is projected to become the second leading cause of cancer death by 2030. The overall 5-year survival rate is about 10% and the poor prognosis is attributed to failure in an early diagnosis, when the tumor would be surgically resectable, its propensity to disseminate, and its resistance to chemo, radio and immunotherapies. For these reasons, innovative and effective therapies that can be rapidly translated to clinical practice represent an urgent medical need. Through a SERological Proteome Analysis we have identified a dozen antigens expressed by PDAC cancer cells and recognized by autoantibodies present in the sera of PDAC patients, but not in the sera of patients with other tumors, or affected by pancreatitis, or healthy donors. One of these antigens, alpha-enolase (ENO1), is recognized by more than 60% of PDAC patients, which also displayed T cells able to specifically being activated by ENO1. We used genetically engineered mice, that develop autochthonous lethal pancreatic carcinomas with different kinetics, to evaluate the protective effect of a DNA vaccine expressing human full-length ENO1. ENO1 DNA vaccine elicited an integrated humoral and cellular immune response that significantly extends mouse survival (Cappello et al., Gastroenterology 2013; DOI: 10.1053/j. gastro.2013.01.020). Unfortunately, after few months the immune pressure on tumors decline as consequence of the increase in myeloid suppressor and T regulatory cells. To overcome this problem, different strategies are ongoing: we are combining ENO1 vaccine with other antigens such as Ezrin, or with chemotherapy, or inhibitors of specific suppressive pathways (Figure 1). 

Notably, combining ENO1 DNA vaccine with chemotherapy treatment significantly enhanced antitumor responses and efficacy to counteract tumor progression compared the vaccine or the chemotherapy alone. Indeed, the robust integrated cellular and humoral immune response led to a reduction of pancreatic tumor lesions (Mandili et al., JITC 2020 DOI: 10.1136/jitc-2020- 001071, Figure 2). 

In the recent years, the global scientific interest focused on the characterization of the crosstalk between immune, stromal and cancer cells. We have revealed how a cytokine, messenger between immune and non-immune cells, is profoundly changing the transcription and secretome profile of cancer-associated fibroblast. This has the consequence of re-shape also the immune cell infiltrate, and globally the tumor microenvironment (Figure 3), and lead to a major pressure on cancer cells (Mucciolo et al., PNAS 2021; DOI: 10.1073/pnas.2020395118).