1. Knocking down of Xkr8 enhances chemotherapy efficacy through modulating tumor immune microenvironment.
- Author
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Chen Y, Chen CY, Huang H, Luo Z, Mu Y, Li S, Huang Y, and Li S
- Subjects
- Animals, Cell Line, Tumor, Humans, Apoptosis drug effects, Gene Knockdown Techniques, Mice, CD8-Positive T-Lymphocytes drug effects, CD8-Positive T-Lymphocytes immunology, Female, Killer Cells, Natural immunology, Killer Cells, Natural drug effects, Mice, Inbred C57BL, Antineoplastic Agents pharmacology, Antineoplastic Agents administration & dosage, Antineoplastic Agents therapeutic use, Macrophages drug effects, Macrophages immunology, Tumor Microenvironment drug effects, Tumor Microenvironment immunology, Fluorouracil administration & dosage, Fluorouracil pharmacology, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms immunology, Pancreatic Neoplasms genetics, Pancreatic Neoplasms pathology, RNA, Small Interfering administration & dosage
- Abstract
Scramblase Xk-related protein 8 (Xkr8) regulates the externalization of phosphatidylserine (PS) during apoptosis and holds a pivotal role in fostering tumor immunosuppression. Targeting Xkr8 in conjunction with chemotherapy demonstrated a novel avenue for amplifying antitumor immune response and overcoming chemo-immune resistance. Here we further evaluated this strategy by using a clinically relevant orthotopic model and elucidated the mechanism through in-depth single-cell RNA sequencing (scRNA-seq). We found that Xkr8 knockdown exhibited the potential to lead to immunogenic cell death (ICD) by impeding the normal clearance of apoptotic cells. Co-delivery of Xkr8 small interference RNA (siRNA) and a prodrug conjugate of 5-fluorouracil (5-Fu) and oxoplatin (FuOXP) showed remarkable therapeutic efficacy in an orthotopic pancreatic tumor model with increased infiltration of proliferative NK cells and activated macrophages in the tumor microenvironment (TME). Single-cell trajectory analysis further unveiled that tumor infiltrating CD8
+ T cells are differentiated favorably to cytotoxic over exhausted phenotype after combination treatment. Our study sheds new light on the impact of Xkr8 knockdown on TME and solidifies the rationale of combining Xkr8 knockdown with chemotherapy to treat various types of cancers., (Copyright © 2024 Elsevier B.V. All rights reserved.)- Published
- 2024
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