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

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.

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Publication Details

Journal
Cancer Research
Published
2025-04-29
DOI
https://doi.org/10.1158/0008-5472.can-24-2021
Citations
11
Primary Topic
Lung Cancer Treatments and Mutations
Type
article
Field-Weighted Citation Impact
16.70

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article

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

Lan Wang, Jianmin Fang, Jieer Ying, Yun Xing et al.
11 citations
Cancer Research
Lung Cancer Treatments and Mutations
16.70
article

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

Lan Wang, Jianmin Fang, Jieer Ying, Yun Xing, Takaya Shimura, Xuefei Tian, Mengyang Fan, Ziwen Zhang, Teng Yang, Peng Guo, Yuxuan Yang, Xiangdong Cheng, Ye Lu, Jiayu Zhu, Meng Li, Yuchao Zhang, Zhiwei Cao, Qing Wei, Xiu Zhu, Y. Li, Fei Wang, Xu Xue, Chuanfei Yu
article en
11 citations

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.

Cancer ResearchVol. 85(11)
Zhejiang Chinese Medical University (CN), Tongji University (CN), University of Science and Technology of China (CN), Tianjin University (CN), Zhejiang University of Science and Technology (CN), Tianjin Foreign Studies University (CN), National Medical Products Administration (CN), Fudan University (CN), Nagoya City University (JP), Zhejiang Cancer Hospital (CN), Peer Intelligence Technology (China) (CN), Hangzhou Academy of Agricultural Sciences (CN), National Institutes for Food and Drug Control (CN), University of Chinese Academy of Sciences (CN), Hangzhou Cancer Hospital (CN)
National Natural Science Foundation of China, National Key Research and Development Program of China, Natural Science Foundation of Zhejiang Province
Good health and well-being
Openalex Percentile: Top 1%
Lung Cancer Treatments and Mutations
16.70
DOIOpen Access PDFOpenAlex
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