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

Cancer Res. 2025 Jun 2;85(11):2081-2099. doi: 10.1158/0008-5472.CAN-24-2021.

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.

MeSH terms

  • 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

Substances

  • Trastuzumab
  • Immunoconjugates
  • trastuzumab deruxtecan
  • Camptothecin