Perivascular Niche–Resident Alveolar Macrophages Promote Interstitial Pneumonitis Related to Trastuzumab Deruxtecan Treatment
Qing Wei, Teng Yang, Ziwen Zhang, Fei Wang, Yuxuan Yang, Jiayu Zhu, Xiu Zhu, Y. Li, Yun Xing, Ye Lu, Xuefei Tian, Mengyang Fan, Yuchao Zhang, Xu Xue, Meng Li, Chuanfei Yu, Lan Wang, Takaya Shimura, Jianmin Fang, Zhiwei Cao, Jieer Ying, Peng Guo, Xiangdong Cheng
Abstract
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.