Bonner Melissa, Askew David, Sathish Kumar Vrishabhadev, Tomchuck Suzanne L, Eid Saada, Abiff Muta, Myers Jay T, Nguyen Phuong, Garyu Justin W A, Miller Tyler E, Huang Alex Yee-Chen
Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
J Immunother Cancer. 2025 Jun 23;13(6):e011815. doi: 10.1136/jitc-2025-011815.
Tumor-associated myeloid cells (TAMCs) are an abundant, phenotypically plastic cell population that is critical for initiating a robust antitumor response. To properly combat cancer cells, TAMCs must sense and transduce both soluble and vital biophysical cues imparted by the dense extracellular matrix (ECM) of the tumor microenvironment (TME). Despite ample research enumerating the deleterious effects of a primary tumor's ECM on TAMCs' functionality, few studies have evaluated the contribution of mechanosensitive cation channel(s) underlying these detrimental changes.
Our study aimed to evaluate the significance of the mechanosensitive cation channel PIEZO1 in TAMCs' phenotype and effector functionality. To do so, we generated CD11b-conditional knockout mice, orthotopically inoculated them with rhabdomyosarcoma 76-9, an aggressive syngeneic rhabdomyosarcoma cell line, and evaluated tumor burden, pan-immune compartment changes, and intrinsic myeloid and lymphoid transcriptomic and functional changes.
Genetic deletion of in CD11b-expressing cells significantly hindered primary and metastatic tumor burden. Intratumorally, we observe enhanced infiltration of CD11b+ dendritic cells (DCs) and CD8+, but not CD4+, T cells. This phenotype was driven by CD11b+ DCs that have undergone transcriptional changes related to improved antigen presentation and T cell activation. Despite being canonically inefficient cross-presenters in the wildtype state, KO CD11b+ DCs, specifically the cDC2A subpopulation, efficiently cross-prime CD8+ T cells on exposure to exogenous particulate antigens.
Here, we report for the first time an association between mechanosensation and cross-presentation by cDC2A cells. Our findings may be impactful to improving the continued development of DC vaccines whose success hinges on proper antigen processing and presentation to cytotoxic T cells in the TME.
肿瘤相关髓样细胞（TAMCs）是一种数量丰富、表型具有可塑性的细胞群体，对启动强大的抗肿瘤反应至关重要。为了有效对抗癌细胞，TAMCs必须感知并转导由肿瘤微环境（TME）致密的细胞外基质（ECM）传递的可溶性和重要生物物理信号。尽管有大量研究列举了原发性肿瘤ECM对TAMCs功能的有害影响，但很少有研究评估这些有害变化背后机械敏感阳离子通道的作用。
我们的研究旨在评估机械敏感阳离子通道PIEZO1在TAMCs表型和效应功能中的重要性。为此，我们构建了CD11b条件性敲除小鼠，将侵袭性同基因横纹肌肉瘤细胞系横纹肌肉瘤76 - 9原位接种到这些小鼠体内，并评估肿瘤负荷、全免疫区室变化以及内在髓样和淋巴样转录组及功能变化。
在表达CD11b的细胞中进行基因敲除显著阻碍了原发性和转移性肿瘤负荷。在肿瘤内，我们观察到CD11b + 树突状细胞（DCs）和CD8 + T细胞（而非CD4 + T细胞）的浸润增强。这种表型是由经历了与改善抗原呈递和T细胞激活相关转录变化的CD11b + DCs驱动的。尽管在野生型状态下通常是低效的交叉呈递细胞，但敲除CD11b的DCs，特别是cDC2A亚群，在接触外源性颗粒抗原时能有效地交叉启动CD8 + T细胞。
在此，我们首次报道了机械感觉与cDC2A细胞交叉呈递之间的关联。我们的发现可能对改善DC疫苗的持续开发具有重要意义，DC疫苗的成功取决于在TME中正确的抗原加工和呈递给细胞毒性T细胞。
