Abstract P3-07-17: Nanosecond Electric Pulses Modify Breast Tumor Microenvironment to Promote Antitumor Immunity

Abstract

Abstract Cancer immunotherapy has had a significant impact on the management of many types of solid tumors. While some patients respond favorably to it, a significant number of patients do not respond or initially respond but develop resistance later, highlighting an unmet need to improve the effectiveness of this treatment. Cancers with intrinsic resistance include breast cancer, not only respond poorly to single agent immunotherapy, but also often show no durable response. Tumor microenvironment (TME) plays a critical role in both pre-existing and acquired immune resistance which is responsible for the low immunogenicity of cancers. We previously reported that an electrical engineering technology generating nanosecond length electric pulses (nsEP) can greatly enhance the immunogenicity of poorly immunogenic cancers including 4T1 breast and Pan02 pancreatic in animal models. To understand how nsEPs overcome predominant immunosuppression in the TME to induce a strong immune response, we further investigated the effects of nsEPs on the breast TME by performing transcriptomic and immune profiling of 4T1 breast cancer cells treated with nsEP. RNAseq data and cell death signaling results demonstrated that nsEPs induced regulated necrotic cell death rather than apoptosis. NsEPs-treated cancer cells greatly decreased angiogenic factors and multiple chemoattracts for myeloid-derived suppressor cells (MDSCs) and macrophages. On the other hand, nsEP-treated cancer cells significantly upregulated chemoattracts for T lymphocytes and a number of proinflammatory/immunostimulatory cytokines. Flow cytometry analysis showed that the dynamic changes of TME following nsEP treatment included: (1) the significant reduction of immunosuppressive cells (MDSCs, Tregs and TAMs); (2) the preservation of cytotoxic CD8+ T cells and conventional CD4+ T cells; and (3) a persistent elevation in cytotoxic cells vs Treg ratio and tissue resident memory CD8+ T cells. Taken together, our results suggest nsEP is a TME modifier that can potentially overturn the immunosuppressive hurdle in the TME to promote antitumor immunity. Citation Format: Lifang Yang, Anthony Nanajian, Stephen Beebe, Siqi Guo. Nanosecond Electric Pulses Modify Breast Tumor Microenvironment to Promote Antitumor Immunity [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-07-17.