The effects of T-DXd on the expression of HLA class I and chemokines CXCL9/10/11 in HER2-overexpressing gastric cancer cells.

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.

• Authors: Shotaro Nakajima, Kosaku Mimura, Takuro Matsumoto, Aung Kyi Thar Min, Misato Ito, Hiroshi Nakano, Prajwal Neupane, Yasuyuki Kanke, Hirokazu Okayama, Motonobu Saito, Tomoyuki Momma, Yohei Watanabe, Hiroyuki Hanayama, Suguru Hayase, Zenichiro Saze, Koji Kono
• Journal: Scientific reports (Sci Rep) Vol. 11 Issue 1 Pg. 16891 (08 19 2021) ISSN: 2045-2322 [Electronic] England
• PMID: 34413454 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s).

Chemical References

• Chemokine CXCL10
• Chemokine CXCL11
• Chemokine CXCL9
• Chemotactic Factors
• Histocompatibility Antigens Class I
• Immunoconjugates
• RNA, Messenger
• trastuzumab deruxtecan
• Receptor, ErbB-2
• Trastuzumab
• Camptothecin

Topics

• Camptothecin (analogs & derivatives, pharmacology, therapeutic use)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Chemokine CXCL10 (genetics, metabolism)
• Chemokine CXCL11 (genetics, metabolism)
• Chemokine CXCL9 (genetics, metabolism)
• Chemotactic Factors (pharmacology)
• DNA Damage
• Gene Expression Regulation, Neoplastic (drug effects)
• Histocompatibility Antigens Class I (metabolism)
• Humans
• Immunoconjugates (pharmacology, therapeutic use)
• RNA, Messenger (genetics, metabolism)
• Receptor, ErbB-2 (metabolism)
• Stomach Neoplasms (drug therapy, genetics, immunology)
• Trastuzumab (pharmacology, therapeutic use)
• Up-Regulation (drug effects)