Oncology Surgery
Cancer-immune system interactions: between active antigen specific immunotherapy and the analysis of tumor microenvironment.
The “Oncology” lab of the ICFS is primarily interested in the clinical application of basic biology advances to surgical oncology. The main field of investigation is represented by tumor immunology with its diagnostic, prognostic and therapeutic implications.
During the past ten years the lab has developed immunotherapy protocols addressing the treatment of advanced melanoma by using a recombinant vaccinia virus (rVV) encoding multiple HLA-A0201 restricted epitopes from tumor associated antigens (TAA) and CD80 and CD86 co-stimulatory molecules. In 2009 we have closed a phase I/II clinical trial based on intranodal administration of this vector in stage III/IV melanoma. No major toxicity was observed following repeated rVV injection. Virus administration was associ- ated with the induction of cytotoxic T lymphocyte (CTL) responses against at least one of the three epitopes from different TAA encoded by the vector. Interestingly, promising clinical results were observed, including one complete response (Fig. 1) of the duration of 19 months in a patient with a stage IV tumor and prolonged overall survival in additional immunologically responsive patients. Capitalizing on these advances similar strategies are presently being developed to address immune-mediated treatments of other cancers, and, in particular, in those expressing cancer/testis TAA of the MAGE-A family in significant percentages of cases (Sadowski-Cron et al., in preparation). Pre-clinical studies have focused on the optimization of conditions favouring the generation of TAA specific CTL responses. In particular, we have dem- onstrated the superior ability of dendritic cells (DC) generated upon culture of peripheral blood monocytes in the presence of IFNα and GM-CSF in the induction of CTL and we have addressed the role of homeostatic cytokines (CK) binding the common γ-chain receptor in the elicitation of anti tumoral responses. We could demonstrate that whereas pre-incubation of CD8+ T lymphocytes in the presence of IL-15 favours the expansion of antigen specific memory cells, culture in the presence of IL-2 predisposes naïve CD8+ lymphocytes to react to TAA derived HLA-restricted epitopes.
The expertise acquired in the characterization of TAA specific immune responses has also been utilized to address the definition of immunogenic epitopes from virus of potential oncogenic significance. We have identified “universal” antigenic peptides derived from human cytomegalovirus (HCMV) pp65 protein, capable of stimulating both HLA class I and class II restricted immune responses, in CD8+ and CD4+ T cells across a wide range of HLA specificities. These reagents might qualify as synthetic immunogens for po- tentially large populations exposed to HCMV infection or reactivation.
An additional productive research line has investigated, in collaboration with the Institute of Pathology of our University, the characteristics of the tumor microenvironment, as related to cancer progression and its clinical features. We have shown that renal cell carcinomas (RCC) do express MICA/B ligands of the natural killer (NK) cell activation marker NKG2D. Importantly, the interaction between tumor and NK cells leads to mutual induction of apoptosis, resulting in a lack of NK cell infiltration into RCC. In other tissues additional immunosuppressive strategies are implemented within tumors to favour escape from immune responses. For instance, we have been able to detect expression of the gene encoding indoleamine 2,3-dioxygenase (IDO), a tryptophan metabolizing enzyme in endothelial and tumor cells in prostate cancers (PCA). By local tryptophan depletion and generation of toxic metabolites this enzyme may contribute to the creation of an immunosuppressive tumoral microenvironment.
Taken together our results underline progress in the “in vitro” and “in vivo” induction of TAA specific immune responses, but also the emerging increasing complexity of the interactions occurring between cancer and in- nate and adaptive immune system. The challenge for the next future is clearly represented by the translation of the knowledge acquired into clini- cal protocols of therapeutic relevance.
Translational science in surgical oncology
The “oncology” lab of the Institute for Surgical Research and Hospital Management enjoys a close relationship with Clinical Surgery Departments. This interaction is consolidated by the presence of clinicians participating full time to the research activities of the lab for periods of time ranging between six months and two years. Clinicians from the Surgical Depart- ments have run clinical trials of active specific immunotherapy in advanced melanoma from the selection of patients to the vaccination procedures and to the comparative evaluation of the clinical course of the disease and the immunological moni- toring. Capitalizing on this model of cooperation, surgeons from different clinics have taken advantage of the technologies and reagents developed within the lab to explore the expression of TAA in lung cancers, to analyze the potentially immunosuppressive features of the tumor microenvironment in the prostate and to address the prognostic relevance of the expression of phenotypic markers of cancer initiating cells in colorectal cancers. In this context, the tight interaction with the Department of Pathology is also proving of critical relevance. Taken together, these studies provide the indispensable background for the development of basic research projects. Furthermore, they allow envisaging innovative strategies of potential clinical relevance as related to the stratification of patients undergo- ing established treatments and to the implementation of novel immunotherapeutic protocols.
