Perivascular Niche–Resident Alveolar Macrophages Promote Interstitial Pneumonitis Related to Trastuzumab Deruxtecan Treatment

• Published in: Cancer research (Chicago, Ill.) Vol. 85; no. 11; pp. 2081 - 2099
• Main Authors: Wei, Qing, Yang, Teng, Zhang, Ziwen, Wang, Fei, Yang, Yuxuan, Zhu, Jiayu, Zhu, Xiu, Li, Yuanzheng, Xing, Yun, Lu, Ye, Tian, Xuefei, Fan, Mengyang, Zhang, Yuchao, Xue, Xiru, Li, Meng, Yu, Chuanfei, Wang, Lan, Shimura, Takaya, Fang, Jianmin, Cao, Zhiwei, Ying, Jieer, Guo, Peng, Cheng, Xiangdong
• Format: Journal Article
• Language: English
• Published: United States 02.06.2025
• Subjects: Animals; Camptothecin - adverse effects; Camptothecin - analogs & derivatives; Disease Models, Animal; Female; Humans; Immunoconjugates - adverse effects; Lung Diseases, Interstitial - chemically induced; Lung Diseases, Interstitial - immunology; Lung Diseases, Interstitial - pathology; Macrophages, Alveolar - drug effects; Macrophages, Alveolar - immunology; Macrophages, Alveolar - metabolism; Macrophages, Alveolar - pathology; Mice; Mice, Inbred C57BL; Trastuzumab - adverse effects
• DOI: 10.1158/0008-5472.CAN-24-2021
• ISSN: 0008-5472; 1538-7445

Trastuzumab deruxtecan (T-DXd) is a transformative HER2-targeting antibody–drug conjugate (ADC) for treating breast cancer. Unfortunately, T-DXd has also been implicated in causing fatal interstitial lung disease (ILD) in multiple clinical trials. A better understanding of the mechanistic basis of these ADC-induced adverse effects could enable development of strategies to prevent or treat T-DXd–related ILD. In this study, we determined that T-DXd–induced ILD represents an off-target adverse event rather than an on-target off-tumor adverse event. To further investigate this phenomenon, an immunocompetent murine model that recapitulates T-DXd–induced ILD events was developed, facilitating in-depth mechanistic studies. Single-cell RNA sequencing in this model implicated alveolar macrophages (AM) as the primary cell type impacted by T-DXd in the lung microenvironment. Intravital microscopy further revealed that AMs resident in perivascular niches directly engulfed blood-circulating T-DXd via Fc–FcγR engagement. This Fc–FcγR interaction with T-DXd triggered a phenotypic shift in AMs from an immunosuppressive to a pro-ILD state, characterized by inflammation and immune activation, mediated through the SPP1 pathways. Finally, mitigating nonspecific T-DXd uptake in the lung by preconditioning perivascular AMs with IgG1 or the parental antibody of T-DXd significantly reduced unintended ADC absorption. These findings elucidate a mechanism by which T-DXd ignites the lung immune microenvironment and underscore the importance of off-target endocytosis by innate immune cells in the development of ADC-related toxicities. Significance: Preconditioning the perivascular niche can prevent lung inflammation induced by antibody-drug conjugate phagocytosis by alveolar macrophages and subsequent SPP1high macrophage differentiation, providing a clinically viable strategy for mitigating interstitial lung disease.