(564) Deep mapping of immune responses against stem cell products in vivo for regenerative medicine

Introduction/Rationale: Cell therapies are a promising approach for the treatment of several human disorders,
including cancer, autoimmune diseases, and regenerative medicine. While several cell therapy
products have proved to be highly functional and are now moving to the clinic, lifelong
immunosuppression is needed to avoid rejection of transplanted cells in patients. Therefore,
the development of new products that offer safe, long-lasting efficacy without the need of
compromising patients’ immune system is still an unmet clinical need. One of the main
challenges is understanding how transplanted cells and the immune system interact,
which will give insight on how rejection is orchestrated and how it could be avoided. To
this end, the aim of this project is to study the immune responses that stem cell-derived
products can elicit in vivo and to identify and exploit novel strategies to protect them in
a cell-autonomous manner.

Methods: To develop a clinically relevant setting, we propose to transplant
murine stem cell-derived beta cells in immunocompetent mice. This will allow, for the first time,
to study the effects of allorejection and autoimmunity, as well as the effects of site of injection
or dose, on survival of grafted cells. Moreover, surviving transplanted cells will be analyzed to
identify new genes or mechanisms that grant immune-evasion or resistance to immune attack.
Finally, our stem cell-derived products will be engineered to target those pathways and
transplanted in vivo to validate their protective effect.

Results: Preliminary data suggest that modulating MHC-I expression can prevent both T cell and NK cell killing.

Conclusion: Altogether, this work will allow to identify novel strategies to improve the clinical translation
of current cell therapy products.