Tiberi Giorgia, Scagliotti Alessandro, Curcio Claudia, Candiello Ermes, Villegas Paula Ariadna Diez, Brugiapaglia Silvia, Mucciolo Gianluca, Roux Cecilia, Castellano Giancarlo, Curto Roberta, Arigoni Maddalena, Calogero Raffaele A, Barutello Giuseppina, Bolli Niccolò, Papotti Mauro Giulio, Adriani Giulia, Novelli Francesco, Cappello Paola
Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.
Hematology Division, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
Clin Transl Med. 2025 Aug;15(8):e70442. doi: 10.1002/ctm2.70442.
The pancreatic tumour microenvironment (TME) is a complex ecosystem where tumour cells, cancer-associated fibroblasts and immune cells interact, often in ways that contribute to tumour growth. The role of interleukin (IL17)A in pancreatic cancer progression is now more defined, and it is known to sustain a pro-tumoural microenvironment and inhibit the immune response. Here, we explore the effect of combining IL17A depletion with a cancer vaccine to enhance anti-tumour immunity.
We used genetically engineered mice proficient or deficient in IL17A, and orthotopically injected mice with pancreatic tumour cells depleted or not in IL17A, to examine the vaccine effects on tumour growth and immune responses. Both humoral and cellular immune responses were analysed following vaccination in IL17A-deficient and control mice.
Mice lacking IL17A-either genetically or through pharmacological depletion-exhibited prolonged survival and smaller tumours, compared to vaccinated controls. Vaccination in IL17A-deficient mice significantly increased the influx of immune cells, including Natural Killer (NK) and effector/memory CD8 T cells, which displayed higher cytotoxic activity. CD8 T-cell depletion in these models notably reduced vaccine efficacy, underscoring the essential role of these cells. NK cell depletion in untreated models further demonstrated NK cells' critical function in controlling tumour growth when IL17A was absent. Overall, IL17A depletion enhanced both antigen-specific humoral and cellular immune responses, indicating a shift towards a more robust and responsive immune environment.
Our findings reveal that the absence of IL17A in the pancreatic TME reprograms it into a more immune-supportive environment, favouring the recruitment of effector/memory immune cells upon vaccination. This approach paves the way for novel therapeutic combinations in pancreatic cancer, where IL17A depletion may boost both immunotherapy efficacy and anti-tumour responses.
胰腺肿瘤微环境（TME）是一个复杂的生态系统，肿瘤细胞、癌症相关成纤维细胞和免疫细胞在其中相互作用，其方式往往有助于肿瘤生长。白细胞介素（IL17）A在胰腺癌进展中的作用现在已更加明确，已知它能维持促肿瘤微环境并抑制免疫反应。在此，我们探讨将IL17A缺失与癌症疫苗联合使用以增强抗肿瘤免疫力的效果。
我们使用了IL17A基因工程改造的野生型或缺陷型小鼠，并将有无IL17A缺失的胰腺肿瘤细胞原位注射到小鼠体内，以研究疫苗对肿瘤生长和免疫反应的影响。在IL17A缺陷型小鼠和对照小鼠接种疫苗后，分析其体液免疫和细胞免疫反应。
与接种疫苗的对照小鼠相比，通过基因缺失或药物去除IL17A的小鼠生存期延长且肿瘤更小。在IL17A缺陷型小鼠中接种疫苗显著增加了免疫细胞的流入，包括自然杀伤（NK）细胞和效应/记忆CD8 T细胞，这些细胞表现出更高的细胞毒性活性。在这些模型中去除CD8 T细胞显著降低了疫苗效力，强调了这些细胞的重要作用。在未处理的模型中去除NK细胞进一步证明了在缺乏IL17A时NK细胞在控制肿瘤生长中的关键功能。总体而言，IL17A缺失增强了抗原特异性体液免疫和细胞免疫反应，表明向更强健且反应灵敏的免疫环境转变。
我们的研究结果表明，胰腺TME中缺乏IL17A会将其重新编程为更有利于免疫的环境，有利于接种疫苗后效应/记忆免疫细胞的募集。这种方法为胰腺癌的新型治疗组合铺平了道路，其中IL17A缺失可能会提高免疫治疗效果和抗肿瘤反应。
