Enhancing the abscopal effect of radiation and immune checkpoint inhibitor therapies with magnetic nanoparticle hyperthermia in a model of metastatic breast cancer

PURPOSE: Enhancing immune responses in triple negative breast cancers (TNBCs) remains a challenge. Our study aimed to determine whether magnetic iron oxide nanoparticle (MION) hyperthermia (HT) can enhance abscopal effects with radiotherapy (RT) and immune checkpoint inhibitors (IT) in a metastatic TNBC model. METHODS: One week after implanting 4T1-luc cells into the mammary glands of BALB/c mice, tumors were treated with RT (3 × 8Gy)±local HT, mild (HT(M), 43°C/20 min) or partially ablative (HT(Abl), 45°C/5min plus 43°C/15min),±IT with anti-PD-1 and anti-CTLA-4 antibodies (both 4 × 10mg/kg, i.p.). Tumor growth was measured daily. Two weeks after treatment, lungs and livers were harvested for histopathology evaluation of metastases. RESULTS: Compared to untreated controls, all treatment groups demonstrated a decreased tumor volume; however, when compared against surgical resection, only RT + HT(M)+IT, RT + HT(Abl)+IT and RT + HT(Abl) had similar or smaller tumors. These cohorts showed more infiltration of CD3(+) T-lymphocytes into the primary tumor. Tumor growth effects were partially reversed with T-cell depletion. Combinations that proved most effective for primary tumors generated modest reductions in numbers of lung metastases. Conversely, numbers of lung metastases showed potential to increase following HT+ IT treatment, particularly when compared to RT. Compared to untreated controls, there was no improvement in survival with any treatment. CONCLUSIONS: Single-fraction MION HT added to RT + IT improved local tumor control and recruitment of CD3(+) T-lymphocytes, with only a modest effect to reduce lung metastases and no improvement in overall survival. HT + IT showed potential to increase metastatic dissemination to lungs.