Abstract 3220: Enhancing breast cancer immunotherapy via IONP-mediated photothermal therapy
Authors: Chen Hongwei , Luan Xin , Paholak Hayley , Burnett Joseph , Stevers Nicholas , Sansanaphongpricha Kanokwan , He Miao , Chang Alfred , Li Qiao , Sun Duxin 
Published: August 2019

Abstract
Despite immunotherapy by harnessing host’s own immune system to fight against cancer has elicited promising durable responses in metastatic melanoma and lung cancer patients, its efficacy in treating breast cancer remains to be low. In this work, we demonstrate that sequential photothermal therapy (PTT), mediated with systemically administered stealthy iron oxide nanoparticles (IONPs), can significantly enhance checkpoint blockade-based immunotherapy for breast cancer. Our data suggests that the combination therapy when combining IONP-mediated PTT with anti-CTLA-4 therapy results in a synergistic antitumor effect to completely inhibit established 4T1 murine breast tumor growth in BALB/c mice, while control treatments, including the antibody alone or IONP-mediated PTT alone, fail to do so. Our data further reveal that the enhanced antitumor effect may be attributed by the effective regulation of the suppressive tumor immunity by IONP-mediated PTT. Our flow cytometry data suggests that CD4+FoxP3+ regulatory T-cells (Tregs) are effectively depleted via IONP-mediated PTT, with a significant reduction of the Treg percentage from 42.2 ± 15.8% (control) to 11.9 ± 6.5% (p &lt; 0.05). Our data further suggest that IONP-mediated PTT significantly reduces suppressor-cell-attractive cytokine granulocyte-colony stimulating factor (G-CSF) secretion, which is the driving force for Treg recruitment. Upon effective regulation of suppressive tumor immunity, the proportion of CD8+ T-cells in tumor tissues is significantly increased from 5.6 ± 2.1% (control) to 37.5 ± 6.9% (p &lt; 0.001) following IONP-mediated PTT. Interestingly, our data suggest that Treg elimination and CD8+ T-cell activation can only be achieved through sequential PTT, not a single dose of PTT, suggesting that the suppressive contribution from the newly responding immune cells following initial antitumor treatment, and the sequential PTT may provide an effective way to not only deplete primary resident suppressive cells, but also newly responding ones. Our data further suggests that the combination therapy against primary tumors elicits a systemic immune rejection of cancer cells at distal sites, while this dramatic immune response is lost when CD8+ T-cells are depleted using anti-CD8 antibody, suggesting the immune rejection triggered by IONP-mediated PTT is through CD8+ T-cell-mediated immune responses. Our data also suggests that the majority of the combination treatment-cured mice can reject re-challenged 4T1 cancer cells, indicating memory T-cell immune surveillance. In conclusion, this study may provide an effective and translational nanomedicine-based strategy to effectively regulate suppressive tumor immunity and turn “cold” breast tumors into “hot”, thereby to significantly enhance checkpoint blockade-based breast cancer immunotherapy.
Citation Format: Hongwei Chen, Xin Luan, Hayley Paholak, Joseph Burnett, Nicholas Stevers, Kanokwan Sansanaphongpricha, Miao He, Alfred Chang, Qiao Li, Duxin Sun. Enhancing breast cancer immunotherapy via IONP-mediated photothermal therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3220.