Forced intracellular degradation of xenoantigens as a modality for cell-based cancer immunotherapy

Summary: Given recent leverage of mesenchymal stromal cells (MSCs) as a potent vaccination platform, we investigated whether forced degradation of an expressed experimental antigen fused to small degron sequences could prime potent antitumoral responses. Retrovirally gene-engineered MSCs were evaluated for their in-vitro antigen presentation capacity, nature of generated peptide repertoire and therapeutic potency in syngeneic immunocompetent mice with pre-established solid T cell lymphoma. Despite lack of noticeable changes in gene expression, MSC-UBvR-OVA vaccination triggered potent T cell activation which can be attributable to the enriched cell surface presentation of OVA-derived peptides added to elevated mitochondrial reactive oxidative species (ROS) production, the latter being associated with efficient antigen processing. Where MSC-UBvR-OVA vaccination successfully controlled tumor growth in cancer-bearing mice, the effect is further enhanced using tranylcypromine-stimulated MSCs and anti-PD-1 combination. Such anti-tumoral response relies on efferocytosis by endogenous phagocytes. Altogether, UBvR facilitated forced antigen degradation represents a plausible modality for future development of tumor antigen-expressing MSC-based vaccine.