Towards nanomedicines mimicking antitumor effector immunity

Anticancer immunotherapeutic strategies (e.g. PD1‐PDL1 blockade) frequently aim to enhance CD8+ cytotoxic T cells to target and eliminate tumor cells. Following cancer cell recognition, these cytotoxic T cells are crucial via delivering a set of serine proteases called granzymes inside tumor cells via the pore‐forming protein perforin at the immunological synapse. In humans five different granzymes have been identified that display distinct primary substrate specificity, i.e. granzymes A, B, H, K, and M. Once inside the tumor cell cytoplasm, all these granzymes can cleave death substrates to initiate a panoply of only partially overlapping cell death pathways.

However, during anticancer immunotherapy in many patients, cancer cells can escape from CD8+ T cell recognition and killing, e.g. via down‐regulation of major histocompatibility complex class I (MHC‐I) molecules or via other T cell‐dysfunctioning strategies coming from the tumor microenvironment. This is a major problem, since the killing programs in cancer cells will therefore not be initiated by the granzymes.In this proposal, we will investigate a novel targeted and personalized anticancer nanomedicine proof‐ofconcept that mimics the effector function of our immune system to kill tumor cells. To overcome cancer immune evasion strategies like MHC‐I downregulation or PDL1 expression, isolated pro‐apoptotic granzymes of cytotoxic cells will be loaded in poly (D,L‐lactic‐co‐glycolic‐co‐hydroxymethyl glycolic acid) (PLGHMGA) nanoparticles for targeted tumor cell killing. For proof‐of‐concept, these nanoparticles will be decorated with anti‐Her2 nanobodies to specifically target Her2+ breast cancer cells. Orchestrating the granzyme composition in nanoparticles further allows us to trigger the desired cell death pathways to bypass potential tumor‐encoded inhibitors of apoptosis or granzyme inhibitors for personalized anticancer therapy.

In this proposal, we will investigate a novel targeted and personalized anticancer nanomedicine proof‐ofconcept that mimics the effector function of our immune system to kill tumor cells. To overcome cancer immune evasion strategies like MHC‐I downregulation or PDL1 expression, isolated pro‐apoptotic granzymes of cytotoxic cells will be loaded in poly(D,L‐lactic‐co‐glycolic‐co‐hydroxymethyl glycolic acid) (PLGHMGA) nanoparticles for targeted tumor cell killing. For proof‐of‐concept, these nanoparticles will be decorated with anti‐Her2 nanobodies to specifically target Her2+ breast cancer cells. Orchestrating the granzyme composition in nanoparticles further allows us to trigger the desired cell death pathways to bypass potential tumor‐encoded inhibitors of apoptosis or granzyme inhibitors for personalized anticancer therapy.

Contact
Azadeh Lotfalikhani