Document Type

Article

Publication Date

2024

Publication Title

Vaccines

Volume

12

Issue

6

Pages

633 (1-15)

DOI

10.3390/vaccines12060633

Abstract

We previously reported that nano-pulse treatment (NPT), a pulsed power technology, resulted in 4T1-luc mammary tumor elimination and a strong in situ vaccination, thereby completely protecting tumor-free animals against a second live tumor challenge. The mechanism whereby NPT mounts effective antitumor immune responses in the 4T1 breast cancer predominantly immunosuppressive tumor microenvironment (TME) remains unanswered. In this study, orthotopic 4T1 mouse breast tumors were treated with NPT (100 ns, 50 kV/cm, 1000 pulses, 3 Hz). Blood, spleen, draining lymph nodes, and tumors were harvested at 4-h, 8-h, 1-day, 3-day, 7-day, and 3-month post-treatment intervals for the analysis of frequencies, death, and functional markers of various immune cells in addition to the suppressor function of regulatory T cells (Tregs). NPT was verified to elicit strong in situ vaccination (ISV) against breast cancer and promote both acute and long-term T cell memory. NPT abolished immunosuppressive dominance systemically and in the TME by substantially reducing Tregs, myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs). NPT induced apoptosis in Tregs and TAMs. It also functionally diminished the Treg suppression capacity, explained by the downregulation of activation markers, particularly 4-1BB and TGFβ, and a phenotypic shift from predominantly activated (CD44+CD62L−) to naïve (CD44−CD62L+) Tregs. Importantly, NPT selectively induced apoptosis in activated Tregs and spared effector CD4+ and CD8+ T cells. These changes were followed by a concomitant rise in CD8+CD103+ tissue-resident memory T cells and TAM M1 polarization. These findings indicate that NPT effectively switches the TME and secondary lymphatic systems from an immunosuppressive to an immunostimulatory state, allowing cytotoxic T

Rights

© 2024 by the authors.

This article is an open access article under the terms and conditions of the Creative Commons Attribution 4.0 International (CC BY 4.0) license.

Data Availability

Article states: "Data are contained within the article."

Original Publication Citation

Nanajian, A., Scott, M., Burcus, N. I., Ruedlinger, B. L., Oshin, E. A., Beebe, S. J., & Guo, S. (2024). Nano-pulse treatment overcomes the immunosuppressive tumor microenvironment to elicit in situ vaccination protection against breast cancer. Vaccines, 12(6), 1-15, Article 633. https://doi.org/10.3390/vaccines12060633

ORCID

0000-0003-0853-8641 (Nanajian), 0000-0002-0672-2202 (Ruedlinger), 0000-0002-2932-9470 (Oshin), 0000-0002-6075-9452 (Beebe), 0000-0002-7280-7888 (Guo)

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