New insights in cancer immunotherapy targeting the immune checkpoint PD-L1
(2022)
Files
ThesisPierre-FlorentPetit_Final.pdf
Restricted Access - Adobe PDF
- 27.94 MB
Details
- Authors
- Supervisors
- Abstract
- Immunotherapy based on monoclonal antibodies targeting the immune checkpoints PD-1 and PD-L1 has revolutionized the treatment of cancer over the last decade. Notwithstanding this success in the clinic, our understanding of the mode of action of anti-PD-1/L1 therapies is still evolving, and the recent literature has brought major revisions in the field. During this work, we first designed a new therapeutic approach to deliver anti-PD-L1 treatment. We engineered tumor-specific CD8 T cells for the intratumoral delivery of an anti-PD-L1 blocking nanobody in a mouse tumor model. We demonstrated the therapeutic superiority of this approach as compared to the systemic injection of anti-PD-L1 antibody, which is the current mode of administration in cancer patients. Our strategy allowed an excellent distribution of anti-PD-L1 nanobody on PD-L1-expressing cells at the tumor site, while systemically injected antibody was trapped in the vicinity of blood vessels. Our results therefore shed light on the poor intratumoral penetration of anti-PD-L1 antibody and suggested that this phenomenon is limiting therapeutic efficacy. Furthermore, we showed that our targeted delivery approach reduced systemic exposure to PD-L1 blocking therapy, which might reduce the risk of developing auto-immune side effects. In parallel, we studied the suppressive activity of PD-L1 in tumor cells and in myeloid cells. Using two different approaches, our results converged to the demonstration that PD-L1 on tumor cells was less potent that PD-L1 on myeloid cells to engage PD-1 on T cells. We hypothesized that PD-L1 on tumor cells might be implicated in protein interactions preventing its binding to PD-1. This led us to suggest a previously unknown protein interaction involving PD-L1 in tumor cells. Finally, we observed that PD-L1 appeared on CD8 T cells upon co-culture with PD-L1-expressing tumor cells. We tried to decipher the mechanisms underlying this intriguing observation, and preliminary results point to a phenomenon of PD-1/PD-L1 mutual exchange between tumor cells and T cells.
- Affiliations
Citations
Petit, P.-F. (2022). New insights in cancer immunotherapy targeting the immune checkpoint PD-L1. https://hdl.handle.net/2078.5/109302