Schulte Ashley J, Lewellen Mitzi, Durose Willa, Nolan Erin, Taghizadeh Leyla, Todhunter Deborah, Bush Courtney, Lang Haeree P, Brown Mary E, DePauw Taylor A, Makielski Kelly M, Kim Jong Hyuk, Burt Lauren E, Overn Paula, Forster Colleen L, Seelig Davis M, O'Sullivan M Gerard, Weigel Brenda J, Murugan Paari, Cutter Gary R, Lund Troy C, Vallera Daniel A, Modiano Jaime F
Animal Cancer Care and Research Program, University of Minnesota, St Paul, Minnesota; Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St Paul, Minnesota; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota; Division of Pediatric, Blood and Masrrow Transplantation, Department of Pediatrics, Medical School, University of Minnesota, Minneapolis, Minnesota.
J Pharmacol Exp Ther. 2025 Sep;392(9):103674. doi: 10.1016/j.jpet.2025.103674. Epub 2025 Aug 18.
We evaluated the antitumor effects of remodeling the MC17 mouse sarcoma microenvironment (SME) by targeting urokinase-type plasminogen activator receptor (uPAR)- and epidermal growth factor receptor (EGFR)-expressing cells. Specifically, we used eBAT (a bispecific ligand-targeted toxin directed to EGFR and uPAR), and its mouse counterpart, meBAT, to ablate uPAR- and/or EGFR-expressing cells. We chose the MC17 model because the cells are resistant to eBAT, allowing us to exclusively evaluate the role of uPAR- and EGFR-expressing cells in the SME. Our results show that uPAR expression, both by the tumor cells and by the SME, was dispensable for tumor formation. However, uPAR-deficient tumors grew considerably slower than uPAR-expressing tumors. To specifically address mechanisms responsible for antitumor effects of remodeling the SME, we used uPAR-knockout bone marrow chimeras. In uPAR-replete chimeras, systemic administration of eBAT or meBAT depleted tumor-associated macrophages, increased the proportion of phagocytic myeloid cells, and promoted T cell infiltration into the SME, which was associated with delayed tumor growth. All of these effects were reduced or abrogated in uPAR-deficient bone marrow chimeras. We conclude that targeting uPAR- and EGFR-expressing stromal cells led to remodeling of the inflammatory SME, diminished tumor-associated immunosuppression, and improved survival of mice with transplantable sarcomas. SIGNIFICANCE STATEMENT: This study demonstrated that targeting urokinase-type plasminogen activator receptor- and/or epidermal growth factor receptor-expressing cells in the sarcoma microenvironment reprograms tumor-associated inflammation, leading to delayed progression in an aggressive, therapy-resistant mouse model of fibrosarcoma. The results indicate that the therapeutic benefit of remodeling the inflammatory microenvironment is achieved by making the tumors more visible to the immune system, highlighting the potential to incorporate this novel strategy into the management of advanced, treatment-refractory sarcomas.
我们通过靶向表达尿激酶型纤溶酶原激活物受体（uPAR）和表皮生长因子受体（EGFR）的细胞，评估了重塑MC17小鼠肉瘤微环境（SME）的抗肿瘤作用。具体而言，我们使用了eBAT（一种靶向EGFR和uPAR的双特异性配体靶向毒素）及其小鼠对应物meBAT，来消除表达uPAR和/或EGFR的细胞。我们选择MC17模型是因为该细胞对eBAT具有抗性，这使我们能够专门评估表达uPAR和EGFR的细胞在SME中的作用。我们的结果表明，肿瘤细胞和SME中uPAR的表达对于肿瘤形成并非必需。然而，缺乏uPAR的肿瘤生长速度明显慢于表达uPAR的肿瘤。为了具体探究负责重塑SME的抗肿瘤作用的机制，我们使用了uPAR基因敲除的骨髓嵌合体。在uPAR充足的嵌合体中，全身给予eBAT或meBAT可使肿瘤相关巨噬细胞减少，吞噬性髓样细胞比例增加，并促进T细胞浸润到SME中，这与肿瘤生长延迟相关。在缺乏uPAR的骨髓嵌合体中，所有这些作用均减弱或消除。我们得出结论，靶向表达uPAR和EGFR的基质细胞可导致炎性SME重塑，减少肿瘤相关的免疫抑制，并提高可移植肉瘤小鼠的生存率。意义声明：本研究表明，在肉瘤微环境中靶向表达尿激酶型纤溶酶原激活物受体和/或表皮生长因子受体的细胞可重新编程肿瘤相关炎症，导致在侵袭性、治疗抵抗性纤维肉瘤小鼠模型中肿瘤进展延迟。结果表明，通过使肿瘤对免疫系统更易见来实现重塑炎性微环境的治疗益处，突出了将这种新策略纳入晚期、治疗难治性肉瘤管理的潜力。
