Hansen Nils, Peña-Martínez Pablo, Skoog Petter, Reinbach Katrin, Hansen Finja C, Faria Susanne Larsson, Grönberg Caitríona, Abdilleh Kawther, Magnusson Susanne, von Wachenfeldt Karin, Millrud Camilla Rydberg, Liberg David, Järås Marcus
Lund Stem Cell Center, Lund University, Lund, Sweden.
Cantargia AB, Lund, Sweden.
J Immunother Cancer. 2024 Dec 18;12(12):e009523. doi: 10.1136/jitc-2024-009523.
Pancreatic ductal adenocarcinoma (PDAC) represents a major clinical challenge due to its tumor microenvironment, which exhibits immune-suppressive properties that facilitate cancer progression, metastasis, and therapy resistance. Interleukin 1 (IL-1) signaling has been implicated as a driver in this process. Mechanistically, both IL-1α and IL-1β bind to the IL-1 receptor type 1, forming a complex with IL-1-receptor accessory protein (IL1RAP), which triggers downstream signaling pathways. The IL1RAP blocking antibody nadunolimab is currently in clinical development, but the precise consequences of inhibiting IL-1 signaling in PDAC remains elusive.
To evaluate the biological relevance of blocking IL1RAP using nadunolimab in a PDAC animal model, human PDAC cells and cancer-associated fibroblasts (CAFs) were co-transplanted into mice. To study the underlying mechanisms of IL1RAP blockade ex vivo, co-cultured PDAC cells and CAFs were treated with nadunolimab prior to RNA sequencing. Migration assays were performed to assess how nadunolimab affects interactions between CAFs and myeloid immune cells. Finally, to establish a clinical correlation between IL1RAP expression and nadunolimab treatment effects, we analyzed tumor biopsies from a clinical phase I/II study in which nadunolimab was administered to patients.
In the xenograft mouse model, nadunolimab exhibited antitumor effects only when human CAFs were co-transplanted with PDAC cells. IL-1 stimulation induced CAFs to secrete chemokines that recruited neutrophils and monocytes. The secretion of this chemokine and the migration of myeloid cells were inhibited by nadunolimab. Media conditioned by IL-1-stimulated CAFs sustained a neutrophil population with a tissue invasion phenotype, an effect that was reversed by nadunolimab. In a cohort of metastatic late-stage PDAC patients receiving nadunolimab as monotherapy, high IL1RAP expression in tumors was associated with extended progression-free survival.
Our study demonstrates that targeting IL1RAP on CAFs inhibits IL-1-induced chemokine secretion and recruitment of neutrophils and monocytes, thereby counteracting the immunosuppressive microenvironment in PDAC. These findings highlight the therapeutic potential of targeting IL1RAP in PDAC.
胰腺导管腺癌（PDAC）因其肿瘤微环境而成为一项重大临床挑战，该肿瘤微环境具有免疫抑制特性，可促进癌症进展、转移及治疗抵抗。白细胞介素1（IL-1）信号传导被认为是这一过程的驱动因素。从机制上讲，IL-1α和IL-1β均与1型IL-1受体结合，与IL-1受体辅助蛋白（IL1RAP）形成复合物，从而触发下游信号通路。IL1RAP阻断抗体纳杜利单抗目前正处于临床开发阶段，但在PDAC中抑制IL-1信号传导的确切后果仍不清楚。
为了评估在PDAC动物模型中使用纳杜利单抗阻断IL1RAP的生物学相关性，将人PDAC细胞和癌症相关成纤维细胞（CAFs）共同移植到小鼠体内。为了在体外研究IL1RAP阻断的潜在机制，在进行RNA测序之前，用纳杜利单抗处理共培养的PDAC细胞和CAFs。进行迁移试验以评估纳杜利单抗如何影响CAFs与髓样免疫细胞之间的相互作用。最后，为了建立IL1RAP表达与纳杜利单抗治疗效果之间的临床相关性，我们分析了一项临床I/II期研究中的肿瘤活检样本，该研究中对患者施用了纳杜利单抗。
在异种移植小鼠模型中，仅当人CAFs与PDAC细胞共同移植时，纳杜利单抗才表现出抗肿瘤作用。IL-1刺激诱导CAFs分泌趋化因子，募集嗜中性粒细胞和单核细胞。纳杜利单抗可抑制这种趋化因子的分泌及髓样细胞的迁移。IL-1刺激的CAFs条件培养基维持了具有组织侵袭表型的嗜中性粒细胞群体，而纳杜利单抗可逆转这一效应。在接受纳杜利单抗单药治疗的转移性晚期PDAC患者队列中，肿瘤中高IL1RAP表达与无进展生存期延长相关。
我们的研究表明，靶向CAFs上的IL1RAP可抑制IL-1诱导的趋化因子分泌以及嗜中性粒细胞和单核细胞的募集，从而对抗PDAC中的免疫抑制微环境。这些发现突出了靶向IL1RAP在PDAC中的治疗潜力。
