Rannikko Jenna H, Turpin Rita, Boström Pia, Virtakoivu Reetta, Harth Chantal, Takeda Akira, Tamminen Anselm, Koskivuo Ilkka, Hollmén Maija
MediCity Research Laboratory and InFLAMES Flagship, University of Turku, Turku, Finland.
Department of Pathology, TYKS Turku University Hospital, Turku, Finland.
J Immunother Cancer. 2025 May 15;13(5):e011292. doi: 10.1136/jitc-2024-011292.
Tumor-associated macrophages (TAMs) adapt to the tumor microenvironment (TME), either aiding cancer eradication or promoting tumor growth and immune evasion. To manipulate TAMs therapeutically, a deep understanding of their interaction with the TME is essential. This study explores the responsiveness of TMEs to bexmarilimab, a macrophage reprogramming therapy showing clinical benefit in various solid tumors.
We exploited a breast cancer patient-derived explant culture (PDEC) model to characterize bexmarilimab responses in both tumor and adjacent cancer-free tissues by RNA sequencing and multiplex cytokine profiling. Using single-cell RNA sequencing, spatial transcriptomics, and conditioned media treatment, we further investigated the effects of Clever-1+ macrophages and TME features on bexmarilimab sensitivity.
The PDEC model captured key aspects of bexmarilimab's mode of action and validated a gene signature for determining treatment sensitivity. We identified three distinct responses to bexmarilimab in tumors and adjacent cancer-free tissues, shaped by the local microenvironment and macrophage phenotype, origin, and localization. The inflammatory state of the TME emerged as the primary determinant of response. Immune activation occurred in immunologically cold TMEs lacking late-stage activated TAMs, whereas interferon-regulated TMEs exhibited suppressed inflammation. In cancer-free breast tissue, bexmarilimab activated B cell responses independent of treatment sensitivity in the adjacent tumor.
These findings reveal the complexity of TAM targeting in cancer and emphasize the need for patient selection to maximize bexmarilimab's efficacy.
肿瘤相关巨噬细胞（TAMs）适应肿瘤微环境（TME），既可以协助消除癌症，也可以促进肿瘤生长和免疫逃逸。为了从治疗上操控TAMs，深入了解它们与TME的相互作用至关重要。本研究探讨了TME对贝司麦利单抗的反应，这是一种巨噬细胞重编程疗法，在多种实体瘤中显示出临床益处。
我们利用乳腺癌患者来源的外植体培养（PDEC）模型，通过RNA测序和多重细胞因子分析来表征贝司麦利单抗在肿瘤组织和相邻无癌组织中的反应。使用单细胞RNA测序、空间转录组学和条件培养基处理，我们进一步研究了Clever-1+巨噬细胞和TME特征对贝司麦利单抗敏感性的影响。
PDEC模型捕捉到了贝司麦利单抗作用模式的关键方面，并验证了一个用于确定治疗敏感性的基因特征。我们在肿瘤组织和相邻无癌组织中确定了对贝司麦利单抗的三种不同反应，这些反应由局部微环境以及巨噬细胞表型、来源和定位所塑造。TME的炎症状态成为反应的主要决定因素。免疫激活发生在缺乏晚期活化TAMs的免疫冷TME中，而干扰素调节的TME则表现出炎症抑制。在无癌乳腺组织中，贝司麦利单抗激活了B细胞反应，且与相邻肿瘤的治疗敏感性无关。
这些发现揭示了癌症中靶向TAM的复杂性，并强调了进行患者选择以最大化贝司麦利单抗疗效的必要性。
