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

## TL;DR

This study explores using engineered mesenchymal stromal cells to degrade antigens and boost cancer immunotherapy by activating T cells and enhancing tumor control in mice.

## Contribution

Forced antigen degradation using the UBvR degron improves cancer immunotherapy through enhanced T cell activation and synergy with anti-PD-1.

## Key findings

- MSC-UBvR-OVA vaccination activates T cells and increases mitochondrial ROS for efficient antigen processing.
- UBvR degron outperforms RNP4 1–80 in promoting OVA degradation and antigen presentation.
- Combining MSC-UBvR-OVA with anti-PD-1 enhances antitumoral activity in mice.

## Abstract

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.

•The UBvR degron is superior to RNP4 1–80 is promoting OVA degradation•The antigen presenting ability of MSC-UBvR-OVA cells requires ROS production•The MSC-UBvR-OVA cells synergize with anti-PD-1 in priming antitumoral activity

The UBvR degron is superior to RNP4 1–80 is promoting OVA degradation

The antigen presenting ability of MSC-UBvR-OVA cells requires ROS production

The MSC-UBvR-OVA cells synergize with anti-PD-1 in priming antitumoral activity

Cellular therapy; Immunology; Cancer