Trastuzumab deruxtecan (DS-8201a), a HER2-targeting antibody-drug conjugate with 
a topoisomerase I inhibitor exatecan derivative (DX-8951 derivative, DXd), has 
been reported to exert potent antitumor effects in xenograft mouse models and 
clinical trials. In this study, the immune system-activating ability of DS-8201a 
was assessed. DS-8201a significantly suppressed tumor growth in an 
immunocompetent mouse model with human HER2-expressing CT26.WT (CT26.WT-hHER2) 
cells. Cured immunocompetent mice rejected not only rechallenged CT26.WT-hHER2 
cells, but also CT26.WT-mock cells. Splenocytes from the cured mice responded to 
both CT26.WT-hHER2 and CT26.WT-mock cells. Further analyses revealed that DXd 
upregulated CD86 expression on bone marrow-derived dendritic cells (DC) in vitro 
and that DS-8201a increased tumor-infiltrating DCs and upregulated their CD86 
expression in vivo DS-8201a also increased tumor-infiltrating CD8+ T cells and 
enhanced PD-L1 and MHC class I expression on tumor cells. Furthermore, 
combination therapy with DS-8201a and anti-PD-1 antibody was more effective than 
either monotherapy. In conclusion, DS-8201a enhanced antitumor immunity, as 
evidenced by the increased expression of DC markers, augmented expression of MHC 
class I in tumor cells, and rejection of rechallenged tumor cells by adaptive 
immune cells, suggesting that DS-8201a enhanced tumor recognition by T cells. 
Furthermore, DS-8201a treatment benefited from combination with anti-PD-1 
antibody, possibly due to increased T-cell activity and upregulated PD-L1 
expression induced by DS-8201a. Mol Cancer Ther; 17(7); 1494-503. ©2018 AACR.