Abstract
Trastuzumab deruxtecan (T-DXd), a HER2-targeting antibody–drug conjugate with a topoisomerase I inhibitor deruxtecan (DXd), exhibits an excellent anti-tumor effect in previously treated HER2-positive tumors. A recent study demonstrated that T-DXd not only suppressed tumor growth but also enhanced anti-tumor immunity through increasing the number of tumor-infiltrating CD8+ T cells and enhancement of major-histocompatibility-complex class I expression on tumor cells in a mouse model. However, the effect of T-DXd on anti-tumor immune responses in human cancers is largely unknown. We investigated the effect of T-DXd on the expression of HLA class I and CXCL9/10/11, T-cell chemoattractants, in HER2-positive human gastric cancer (GC) cells. We found that T-DXd significantly inhibited GC cell proliferation in a HER2-dependent manner, while it slightly increased the expression of HLA class I in HER2-positive GC cells. Moreover, we revealed that T-DXd significantly induced mRNA expression of CXCL9/10/11 in HER2-positive GC cells. T-DXd-triggered up-regulation of these chemokines was mediated through the activation of DNA damage signaling pathways. These results suggest that T-DXd triggers anti-tumor immune responses at least in part through induction of the expression of HLA class I and CXCL9/10/11 on HER2-positive GC cells, resulting in the enhancement of anti-tumor immunity in human GC.
Highlights
Trastuzumab deruxtecan (T-DXd), a HER2-targeting antibody–drug conjugate with a topoisomerase I inhibitor deruxtecan (DXd), exhibits an excellent anti-tumor effect in previously treated HER2positive tumors
Because DNA damage-induced checkpoint activation is partially regulated by ataxia telangiectasia-and-rad3-related (ATR) and ataxia-telangiectasia mutated (ATM) pathways[31], we examined the involvement of DNA damage signalings such as ATR and ATM pathways in the induction of mRNA expression of CXCL9/10/11 by T-DXd in HER2positive gastric cancer (GC) cells
We identify for the first time the effect of T-DXd on the expressions of human leukocyte antigen (HLA) class I and chemokines, CXCL9/10/11, in HER2-positive GC cells
Summary
Trastuzumab deruxtecan (T-DXd), a HER2-targeting antibody–drug conjugate with a topoisomerase I inhibitor deruxtecan (DXd), exhibits an excellent anti-tumor effect in previously treated HER2positive tumors. T-DXd-triggered up-regulation of these chemokines was mediated through the activation of DNA damage signaling pathways These results suggest that T-DXd triggers anti-tumor immune responses at least in part through induction of the expression of HLA class I and CXCL9/10/11 on HER2-positive GC cells, resulting in the enhancement of anti-tumor immunity in human GC. The increment of tumor-infiltrating dendritic cells and CD8+ T cells, the augmentation of major-histocompatibility-complex (MHC) class I in cancer cells, and the rejection of rechallenged cancer cells by adaptive immune T cells were observed in an immunocompetent mouse model with human HER2-expressing murine colorectal cancer (CRC) cells, which might a reason for a superior anti-tumor effect of T-DXd as compared with trastuzumab alone and T-DM1. Previous reports indicated that topoisomerase I inhibition triggered the activation of DNA damage signaling leading to enhanced expression of MHC class I in cancer cells, which may assist the immune system to eliminate these cells[17,18,19]. Because T-DXd, but not anti-HER2 antibody, has been reported to cause the activation of DNA damage signaling in HER2-positive cancer c ells[1], there is a possibility that T-DXd can increase the expression of HLA class I through the activation of DNA damage signaling
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