Nanajian Anthony, Scott Megan, Burcus Niculina I, Ruedlinger Brittney L, Oshin Edwin A, Beebe Stephen J, Guo Siqi
Frank Reidy Research Center for Bioelectrics, Old Dominion University, Norfolk, VA 23508, USA.
Department of Biological Sciences, Old Dominion University, Norfolk, VA 23529, USA.
Vaccines (Basel). 2024 Jun 7;12(6):633. doi: 10.3390/vaccines12060633.
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 (CD44CD62L) to naïve (CD44CD62L) 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 CD8CD103 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 cell function and immune memory formation to eliminate cancer cells and account for the NPT in situ vaccination.
我们之前报道过，纳米脉冲治疗（NPT）作为一种脉冲功率技术，可消除4T1-luc乳腺肿瘤并产生强大的原位疫苗接种效果，从而完全保护无瘤动物免受第二次活肿瘤攻击。NPT在4T1乳腺癌主要为免疫抑制性的肿瘤微环境（TME）中引发有效抗肿瘤免疫反应的机制仍未得到解答。在本研究中，对原位4T1小鼠乳腺肿瘤进行NPT治疗（100纳秒，50千伏/厘米，1000个脉冲，3赫兹）。在治疗后的4小时、8小时、1天、3天、7天和3个月时间点采集血液、脾脏、引流淋巴结和肿瘤，用于分析各种免疫细胞的频率、死亡情况和功能标志物，以及调节性T细胞（Tregs）的抑制功能。已证实NPT可引发针对乳腺癌的强大原位疫苗接种（ISV），并促进急性和长期T细胞记忆。NPT通过大幅减少Tregs、骨髓来源的抑制性细胞（MDSCs）和肿瘤相关巨噬细胞（TAMs），在全身和TME中消除免疫抑制优势。NPT诱导Tregs和TAMs凋亡。它还在功能上削弱了Treg的抑制能力，这可通过激活标志物（特别是4-1BB和TGFβ）的下调以及从主要为活化型（CD44CD62L）到幼稚型（CD44CD62L）Tregs的表型转变来解释。重要的是，NPT选择性地诱导活化Tregs凋亡，并使效应性CD4和CD8 T细胞免受影响。这些变化随后伴随着CD8CD103组织驻留记忆T细胞的相应增加和TAM M1极化。这些发现表明，NPT有效地将TME和二级淋巴系统从免疫抑制状态转变为免疫刺激状态，使细胞毒性T细胞功能和免疫记忆形成得以消除癌细胞，并解释了NPT原位疫苗接种的现象。
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