Multifaceted approaches to tumor microenvironment modulation and immune checkpoint targeting

Cancer is a complex disease that thrives by creating an environment in the body that fosters its growth and evasion of immune detection. This "tumor microenvironment" (TME) is made up of various cells, extracellular matrix and provides signals that can down-regulate anticancer immune responses. In this thesis, we developed innovative therapeutic strategies to reshape the TME and boost the immune system’s ability to fight cancer.

A major focus of this work was developing novel proteins targeting inhibitory and stimulatory pathways in the TME. As a therapeutic that targets inhibitory pathways, we developed DSP502, which is a bispecific fusion protein that blocks the PD-L1 and PVR immune escape pathways, often exploited by cancer cells. In vitro and in vivo experiments with DSP502 showed promise in reactivating antitumor immunity to attack tumors more effectively.

As a therapeutic that targets stimulatory pathways, we developed CD27xEGFR, a bispecific antibody which activates immune cells via CD27 co-stimulation specifically at the tumor site via EGFR anchoring. In vitro experiments with CD27xEGFR showed its promise in reducing potential side effects and in enhancing adaptive immune responses in cancers that overexpress the EGFR protein.

Lastly, we identified CD300a—a molecule expressed by innate immune cells and known to negatively regulate immunity—as a promising target for enhancing innate immune responses in cancers such as lymphomas and uveal melanoma.

In conclusion, these findings demonstrate that protein engineering strategies and identification of new targets may be help overcome challenges posed by the TME and pave the way for re-activating anti-cancer immunity.