Gobbini Elisa, Hubert Margaux, Doffin Anne-Claire, Eberhardt Anais, Hermet Léo, Li Danlin, Duplouye Pierre, Ghamry-Barrin Sarah, Berthet Justine, Benboubker Valentin, Grimont Maxime, Sakref Candice, Perrot Jimmy, Tondeur Garance, Harou Olivier, Lopez Jonathan, Dubois Bertrand, Dalle Stephane, Caux Christophe, Caramel Julie, Valladeau-Guilemond Jenny
INSERM U1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Univ Lyon, Université Claude Bernard Lyon 1, Lyon, France.
Institut Curie, Oncology Department, Paris, France.
Cancer Immunol Res. 2025 Apr 2;13(4):517-526. doi: 10.1158/2326-6066.CIR-24-0421.
Dendritic cells (DC) are promising targets for cancer immunotherapies because of their central role in the initiation and control of immune responses. The type 1 conventional DC (cDC1) population is of particular interest because of its ability to cross-present antigens to CD8+ T cells. cDC1s also secrete cytokines that allow Th1 cell polarization and NK cell activation and recruitment. However, the spatial organization and specific functions of cDC1s in response to immunotherapy remain to be clearly characterized in human tumors. In this study, we used a multiplexed immunofluorescence analysis pipeline coupled with computational image analysis to determine the spatial organization of cDC1s in skin lesions from a cohort of patients with advanced melanoma treated with immune checkpoint inhibitors (ICI). For this, we performed a whole-slide image analysis of cDC1 infiltration, distribution, and spatial interaction with key immune partners such as CD8+ T cells and plasmacytoid DCs. We also analyzed LAMP3+ DCs, which correspond to a mature subset of tumor-infiltrating DCs. Distance and cell network analyses demonstrated that cDC1s exhibited a scattered distribution compared with tumor-infiltrating plasmacytoid DCs and LAMP3+ DCs, which were preferentially organized in dense areas with high homotypic connections. The proximity and interactions between CD8+ T cells and cDC1s were positively associated with the response to ICIs. In conclusion, our study unravels the complex spatial organization of cDC1s and their interactions with CD8+ T cells in lesions of patients with melanoma, shedding light on the pivotal role of these cells in shaping the response to ICIs.
树突状细胞(DC)是癌症免疫治疗中有前景的靶点,因为它们在免疫反应的启动和控制中起核心作用。1型传统DC(cDC1)群体尤其受关注,因为它能够将抗原交叉呈递给CD8+ T细胞。cDC1还分泌细胞因子,促进Th1细胞极化以及NK细胞的激活和募集。然而,在人类肿瘤中,cDC1对免疫治疗反应的空间组织和特定功能仍有待明确表征。在本研究中,我们使用了多重免疫荧光分析流程结合计算机图像分析,以确定接受免疫检查点抑制剂(ICI)治疗的晚期黑色素瘤患者队列皮肤病变中cDC1的空间组织。为此,我们对cDC1的浸润、分布以及与关键免疫伙伴(如CD8+ T细胞和浆细胞样DC)的空间相互作用进行了全玻片图像分析。我们还分析了LAMP3+ DC,它们对应于肿瘤浸润DC的一个成熟亚群。距离和细胞网络分析表明,与肿瘤浸润的浆细胞样DC和LAMP3+ DC相比,cDC1呈散在分布,后者优先组织在具有高同型连接的密集区域。CD8+ T细胞与cDC1之间的接近程度和相互作用与对ICI的反应呈正相关。总之,我们的研究揭示了黑色素瘤患者病变中cDC1的复杂空间组织及其与CD8+ T细胞的相互作用,阐明了这些细胞在塑造对ICI反应中的关键作用。