Stereotactic ablative radiotherapy and FAPα-based cancer vaccine suppresses metastatic tumor growth in 4T1 mouse breast cancer

Abstract

Background and purposeThis study tested the hypothesis that a novel combination of stereotactic ablation radiotherapy (SABR) and a cancer vaccine against fibroblast activation protein-alpha (FAPα) can suppress established tumor growth and impede potential metastasis. MethodsThe poorly immunogenic metastatic mouse mammary carcinoma 4T1 was used as a model. Mice were randomly assigned to five treatment groups: (1) untreated control, (2) FAPα-based cancer vaccine, (3) SABR, (4) SABR + pCDH (lentiviral control vector), (5) SABR + FAPα-based cancer vaccine (SABR/FAPα-Vax). FAPα-based cancer vaccine were administered subcutaneously every week for a total of three treatments. SABR was delivered to the primary tumor by 3 × 8 Gy after the first vaccination. ResultsConsistent with the poorly immunogenic nature of 4T1, tumor-bearing mice receiving FAPα-based cancer vaccine or SABR monotherapy showed a modest reduction in tumor volume and increased animal lifespan. In contrast, SABR/FAPα-Vax was well-tolerated, significantly reduced tumor burden, and increased survival compared to monotherapy. The increased survival correlated with inhibition of extracellular matrix (ECM) production, tumor vascularization and lymphangiogenesis. SABR/FAPα-Vax also resulted in an abscopal effect capable of eliminating lung metastases. SABR/FAPα-Vax recruited and activated CD8 + T cells to attack tumor cells and FAPα + stromal cells, and initiated suppressor cell reprogramming, including facilitating macrophage polarization toward an anti-tumor (M1) state, as well as depleting myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs). ConclusionThese findings provide a novel therapeutic combination of radiation and FAPα-based cancer vaccine with promising results against poorly immunogenic metastatic cancer. This study may pave the way to overcome the therapeutic resistance caused by FAPα + CAFs.