Stepanechko Mariia, Gamache Awndre, Padilla Frederic, Nemshick Madison, Kitelinger Lydia, Conarroe Claire, DeWitt Matthew, Hossack John A, Bullock Timothy Nj
IEEE Trans Biomed Eng. 2025 May 15;PP. doi: 10.1109/TBME.2025.3568594.
Pancreatic adenocarcinoma (PDAC) tumors are often unresectable and do not respond to standard anti-cancer treatments. Boiling histotripsy (BH) is a mechanical focused ultrasound ablation regimen that can target nonoperable tumors. BH is a non-invasive procedure that might synergize with immunotherapies being developed for PDAC. We reasoned that BH-mediated release of tumor antigen and damage-associated molecular patterns would augment tumor immunity and cooperate with α-CD40 therapy.
We explored the efficacy of BH ablation either as monotherapy for PDAC or in combination with systemically administered αCD40 agonistic antibodies in controlling tumor outgrowth. We further assessed the changes in the tumor immune compartment and the ability of BH to release tumor antigens by flow cytometry.
A single BH treatment could not control tumor growth and had limited independent immunostimulatory properties. BH effectively liberated tumor antigen into the tumor microenvironment for acquisition by local phagocytes but did not promote its presence in the tumor-draining lymph nodes. BH did not activate either tumor- or lymph noderesident conventional dendritic cells. BH did not impede the ability of α-CD40 immunotherapy to reduce the tumor burden and promote the infiltration of M1-like macrophages and IFNγ+ CD8+ T cells to the tumor microenvironment, suggesting that antibody access to the ablated tissue was not obstructed.
Our findings indicate that PDAC tumor progression cannot be halted by BH ablation using sub-total ablation, and that the BH treatment regimen utilized in this study has limited immunogenicity.
胰腺腺癌（PDAC）肿瘤通常无法切除，且对标准抗癌治疗无反应。沸腾组织粉碎术（BH）是一种机械聚焦超声消融疗法，可针对无法手术切除的肿瘤。BH是一种非侵入性手术，可能与正在为PDAC开发的免疫疗法协同作用。我们推测，BH介导的肿瘤抗原释放和损伤相关分子模式会增强肿瘤免疫，并与α-CD40疗法协同作用。
我们探讨了BH消融作为PDAC单一疗法或与全身给药的αCD40激动性抗体联合使用在控制肿瘤生长方面的疗效。我们还通过流式细胞术进一步评估了肿瘤免疫区室的变化以及BH释放肿瘤抗原的能力。
单次BH治疗无法控制肿瘤生长，且独立的免疫刺激特性有限。BH有效地将肿瘤抗原释放到肿瘤微环境中，以供局部吞噬细胞摄取，但并未促进其在肿瘤引流淋巴结中的存在。BH既未激活肿瘤驻留的常规树突状细胞，也未激活淋巴结驻留的常规树突状细胞。BH并未阻碍α-CD40免疫疗法减轻肿瘤负担以及促进M1样巨噬细胞和IFNγ+ CD8+ T细胞浸润到肿瘤微环境中的能力，这表明抗体能够进入消融组织。
我们的研究结果表明，使用次全消融的BH消融无法阻止PDAC肿瘤进展，且本研究中使用的BH治疗方案免疫原性有限。
