In cancer immunotherapy and vaccine field, considerable efforts have been invested to optimize the induction of effector T cells that, by recognizing tumor-specific or pathogen-associated antigens, control tumor cells or infections. Preserving effector T cell function is a major focus of cancer immunotherapy approaches for clinical trials, as is the development of strategies to target regulatory T cells (Tregs) that directly control T cell hypo-responsiveness. In the vaccine field, on the other hand, several strategies have been developed to improve T cell immunogenicity to heterologous antigens expressed by viral vectors. Especially for HIV viral vectors, new vaccine approaches have yielded promising results in primates, although effectiveness was limited in human clinical trials so far.
Tumor-associated neutrophils (TAN) participate in the control of human tumor progression. If and how TAN interact with effector Tregs at distinct tumor stages remains to be determined. TAN signals that may regulate the functional state of tumor T cells must be defined. It is also not known whether Tregs interact with TAN and facilitate their functional switch from antito pro- tumorigenic state.
Distinct neutrophil subtypes are recruited as a result of pro-inflammatory environment during virus infection. Study of the mechanism of neutrophil-dependent control of T cell subset responses to virus-delivered antigens would be of major interest for the generation of viral-based vaccines. The ability of neutrophil subtypes to interact with T cells must be defined to improve the virus-based vaccine efficacy.
Our studies could provide:
• new treatment strategies that prevent TAN dysfunction, Tregs activation and subsequent effector T cell hyporesponsiveness, and thus increase the effectiveness of cancer immunotherapy
• new vaccine approaches to modulate neutrophil subtypes responses to improve antigen-specific T cell responses, and thus increase the effectiveness of HIV vaccines.

Hepatitis B virus (HBV), an hepatotropic non-cytopathic DNA virus, still represents a global health problem, with millions of deaths for year because of complication of chronic infection. Chronic infection and its outcome are believed a consequence of defective antiviral response, mainly in T-cell arm, probably mediated by prolonged exposition to large amounts of viral antigens. Recently, many advancements have been done on virus-specific CD8 dysfunction or “exhaustion”, while far less is known about the role of other components of immune response. Thus, aims of the present proposal are the evaluation of phenotype and function of CD4 T cells and B cells in both acute self-limited HBV infection, and in chronic HBV, in order to identify correlates of protection, and additional markers of immune impairment. The project will focus on multiple immunological parameters: dynamics of CD4 memory development, and lineage differentiation, B cells memory development and antibodies functional assays, in acute self limited infection; degree and role, if any, of CD4 T and B cells exhaustion in chronic infection, with different degree of viral control. The analysis will be conducted on cryopreserved PBMCs samples of patients affected by HBV (acute or chronic) and will be performed by both molecular and cellular approaches. Interestingly, many of them have been developed at the host institution. Thus, in addition to the possibility to develop a challenging project of strong impact, due to training that the host will provide, the permanence at the host institution, where multiple competences of very high scientific level coexist, will represent for the applicant an unique experience for scientific and working career.

More than 25 years after the discovery of human immunodeficiency virus (HIV) as the causative agent of AIDS, the mechanisms governing pathogenesis and disease progression are still not fully understood. Indeed, a progressive impairment of the immune system, with alterations that affect both innate and adaptive immunity, characterizes the infection with HIV 1 in humans and with simian immunodeficiency virus (SIV) in macaques. It has been proposed that a state of chronic immune activation contributes to loss of CD4 T cells and to alterations of immune responses, ultimately leading to disease progression. The loss of CD4+CCR5+ T cells in the gut associated lymphoid tissue (GALT) has been well documented both in natural host and in pathogenic models of SIV infection. A decrease in the frequency of Th17 cells, a newly discovered subset of effector T cells involved in the immune response against extracellular bacteria, has been recently described by the applicant, in the mucosa of SIV infected rhesus macaques. Nevertheless the migratory capacity of this T cell subpopulation has not been investigated so far. Chemokines are important mediators of leukocyte trafficking and function, and deregulation of their expression might contribute in part to the pathogenesis of HIV-1/SIV infection. The aim of this project is to investigate the mechanisms that mediate Th17 cells trafficking and activities at mucosal sites together with their decrease in frequency during HIV/SIV infection in order to better understand the pathogenesis of AIDS, in view of generating efficient vaccines.

Dr. Cecchinato is currently continuing this research with funds obtained from the Swiss National Science Foundation, Swiss HIV Cohort Study (SHCS project N°. 719).