Background - Current anti-tumor therapies and immunotherapies fail due to tumor escape from immune response or to a state of tolerance preventing or dumping activation of immune effector cells. In fact, even when an appropriate priming event takes place in situ and a potent antitumor response is gen¬erated, the effector cell population can revert to a tolerant state. This striking observation demonstrates a critical parameter that must be considered when attempting the immunotherapy of tu¬mors. Both the adoptive transfer of previously activated T cells and the activation of endogenous tumor-specific T cells via vaccination may initially demonstrate potent antitumor activity. This may be reflective of a common observation in clinical trials, presenting as partial or incomplete response among immunotherapy study par¬ticipants. However, unless steps are taken to ensure sustained stim¬ulation of T cells to negate the effects of the immunologically suppressive tumor microenviron¬ment T cells may eventually be rendered tolerant, allowing for uninhibited tumor growth. In the tumor microenvironment dendritic cells (DCs) and their soluble products play a central role in regulating the immune response against tumors and inducing a tolerant state or conversely the activation of immune effector mechanisms. Simultaneously administered immunotherapy may also alter, however temporarily, the balance of factors leading to response or tolerance in the tumor microenvironment and its overall outcome can be in turn dependent upon the complex phenomena taking place in situ.
Preliminary results – Several preliminary observations, already available reagents and experimental procedures will allow the applicants to address the proposed research: 1) stimulation of DCs with different combinations of pathogen associated molecular patterns (PAMPs) allowed us to evidentiate a dissociation in the production of the two proinflammatory cytokines IL-12 and Il-23. Given the divergent role of IL-12 and IL-23 in tumor surveillance, our results suggest that various conditions may reproduce a similar scenario also in the modulation of a response to tumor cells; 2) our studies in a mouse model of myeloma revealed that the subcutaneous microenvironment is the most suitable for induction of a tumor protective CD8+ T-cell memory immune response, likely due to the in situ presence of DCs; 3) previous research led to the development of a whole range of antibodies, “armed” antibodies, transfectants, mouse models which will be instrumental in approaching several aspects of the research.
Project description and objectives - With the research project described herein we aim at elucidating in appropriate in vitro and in vivo models the role of soluble factors and cell-cell interactions in tipping the balance of a prospective anti-tumor immune reaction in the tumor microenvironment towards response or tolerance. In particular we will consider the following aspects: 1) the activation of DC by tumor cells, 2) the opposing role of DC-derived IL-12, IL-23 and IDO in anti-tumor immune responses, 3) the ability of in vivo transferred human immune cells to respond to DC stimuli, 4) the role of passive immunotherapy in altering the relationships between soluble factors and cells in the tumor microenvironment; 5) the influence of microenvironment manipulations on the outcome of immunotherapy regimens.