Musiu Chiara, Adamo Annalisa, Caligola Simone, Agostini Antonio, Frusteri Cristina, Lupo Francesca, Boschi Federico, Busato Alice, Poffe Ornella, Anselmi Cristina, Vella Antonio, Wang Tian, Dusi Silvia, Piro Geny, Carbone Carmine, Tortora Giampaolo, Marzola Pasquina, D'Onofrio Mirko, Crinò Stefano Francesco, Corbo Vincenzo, Scarpa Aldo, Salvia Roberto, Malleo Giuseppe, Lionetto Gabriella, Sartoris Silvia, Ugel Stefano, Bassi Claudio, Bronte Vincenzo, Paiella Salvatore, De Sanctis Francesco
Department of Medicine, Section of Immunology, University of Verona Hospital Trust, Verona, Italy.
Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.
Cancer Lett. 2025 Jan 28;609:217327. doi: 10.1016/j.canlet.2024.217327. Epub 2024 Nov 22.
Pancreatic cancer (PC) is characterised by late diagnosis, tumour heterogeneity, and a peculiar immunosuppressive microenvironment, leading to poor clinical outcomes. Local ablative techniques have been proposed to treat unresectable PC patients, although their impact on activating the host immune system and overcoming resistance to immunotherapy remains elusive.
We dissected the immune-modulatory abilities triggered by local ablation in mouse and human PC models and human specimens, integrating phenotypic and molecular technologies with functional assays.
Local ablation treatment performed in mice bearing orthotopic syngeneic PC tumours triggered tumour necrosis and a short-term inflammatory process characterised by the prompt increase of HMGB1 plasma levels, coupled with an enhanced amount of circulating and tumour infiltrating myeloid cells and increased MHCII expression in splenic myeloid antigen-presenting cells. Local ablation synergised with immunotherapy to restrict tumour progression and improved the survival of PC-bearing mice by evoking a T lymphocyte-dependent anti-tumour immune response. By integrating spatial transcriptomics with histological techniques, we pinpointed how combination therapy could reshape TME towards an anti-tumour milieu characterised by the preferential entrance and colocalization of activated T lymphocytes and myeloid cells endowed with antigen presentation features instead of T regulatory lymphocytes and CD206-expressing tumour-associated macrophages. In addition, treatment-dependent TME repolarization extended to neoplastic cells, promoting a shift from squamous to a more differentiated classical phenotype. Finally, we validated the immune regulatory properties induced by local ablation in PC patients and identified an association of the short-term treatment-dependent increase of neutrophils, NLR and HMGB1 with a longer time to progression.
Therefore, local ablation might overcome the current limitations of immunotherapy in PC.
胰腺癌（PC）的特点是诊断较晚、肿瘤异质性以及特殊的免疫抑制微环境，导致临床预后较差。尽管局部消融技术对激活宿主免疫系统和克服免疫治疗耐药性的影响尚不清楚，但已有人提出用其治疗无法切除的PC患者。
我们在小鼠和人类PC模型以及人类标本中剖析了局部消融引发的免疫调节能力，将表型和分子技术与功能测定相结合。
在原位同基因PC肿瘤小鼠中进行的局部消融治疗引发了肿瘤坏死和短期炎症过程，其特征是HMGB1血浆水平迅速升高，同时循环和肿瘤浸润的髓样细胞数量增加，脾髓样抗原呈递细胞中MHCII表达增加。局部消融与免疫治疗协同作用，通过引发T淋巴细胞依赖性抗肿瘤免疫反应来限制肿瘤进展并提高荷瘤小鼠的生存率。通过将空间转录组学与组织学技术相结合，我们明确了联合治疗如何将肿瘤微环境重塑为抗肿瘤环境，其特征是活化的T淋巴细胞和具有抗原呈递特征的髓样细胞而非调节性T淋巴细胞和表达CD206的肿瘤相关巨噬细胞优先进入并共定位。此外，治疗依赖性的肿瘤微环境重极化扩展到肿瘤细胞，促进了从鳞状细胞向更分化的经典表型的转变。最后，我们验证了局部消融在PC患者中诱导的免疫调节特性，并确定了中性粒细胞、NLR和HMGB1的短期治疗依赖性增加与较长的疾病进展时间之间的关联。
因此，局部消融可能克服目前PC免疫治疗的局限性。
