Details
- ERC sector
- LS6 - Immunity, Infection and Immunotherapy
- ERC subsector
- LS6_2 - Adaptive immunity
- Project start date
- CUP
- D53D23007650006
- Financial support received
- €41.924,00
Description and purpose
Taking advantage of unique mouse models of neonatal HBV infection which are expected to mimic the virologic and immunologic events taking place after vertical transmission, this part of the study focuses on children and young adult HBeAg positive patients with high replication and low inflammation to understand whether CD8+ T cells derived from HBeAg+ and HBeAg- stages of chronic infection display different severity of exhaustion and different underlying mechanistic profiles, in order to define whether immune therapies should be specifically tailored according to the age of the patient and to the stage of chronic infection.
Purpose
The overall goal of the project is to reprogram dysfunctional virus-specific CD8+ T cells from HBeAg+ chronically infected HBV patients into functional cells endowed with potent antiviral activity.
In particular, the exploratory objectives evaluated using the human biological samples collected for this purpose are:
- To define the transcriptional and molecular signature of CD8+ T cell dysfunction in the HBeAg+ stage of HBV infection.
- To validate the capacity of selected therapeutic targeting strategies to reprogram dysfunctional T cells.
Expected results
In addition to fostering new concepts in adaptive immunity and viral pathogenesis in chronic HBV infection, we are confident that results emerging from this proposal will have the potential to instruct the design of novel, rational strategies that direct the immune system to terminate chronic HBV infection and its attendant costs and complications.
Achieved results
Immune checkpoint inhibitors offer limited effects on intrahepatically primed dysfunctional CD8+ T cells. By contrast, we observed that by targeting costimulatory members of the TNF receptor family, particularly 4-1BB, these cells could be transitioned into antiviral effectors. Consistent with this, in HBeAg+ chronic patients, 4-1BB activation showed the highest potential to rejuvenate dysfunctional CD8+ T cells. By contrast, OX40L induced only a modest increase in IFN-g production by CD8+ T cells stimulated with polymerase peptide pools, and PD-1 blockade did not show any effect.
Scientific director
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