Tumor-associated macrophages confer resistance to chemotherapy (Trifluridine/Tipiracil) in digestive cancers by overexpressing thymidine phosphorylase

• Published in: Cancer letters 2024-12, Vol.606, p.217307, Article 217307
• Main Authors: Malier, Marie, Laverriere, Marie-Hélène, Henry, Maxime, Yakoubi, Malika, Bellaud, Pascale, Arellano, Cécile, Sébillot, Anthony, Thomas, Fabienne, Josserand, Véronique, Girard, Edouard, Roth, Gael S., Millet, Arnaud
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Cancer; Cell Line, Tumor; Chemoresistance; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - enzymology; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; Drug Combinations; Drug Resistance, Neoplasm; Humans; Life Sciences; Mice; Pyrimidine metabolism; Pyrrolidines - pharmacology; Thymidine phosphorylase; Thymidine Phosphorylase - genetics; Thymidine Phosphorylase - metabolism; Thymine - pharmacology; Trifluridine - pharmacology; Tumor-associated macrophages; Tumor-Associated Macrophages - drug effects; Tumor-Associated Macrophages - metabolism; Uracil - analogs & derivatives; Uracil - pharmacology; Xenograft Model Antitumor Assays
• ISSN: 0304-3835; 1872-7980; 1872-7980
• DOI: 10.1016/j.canlet.2024.217307

Pyrimidine analogs are part of the first-line chemotherapy regimen for gastrointestinal cancers. Trifluridine combined with tipiracil, a specific thymidine phosphorylase inhibitor, in TAS-102 has recently emerged as a potential alternative in the face of primary or secondary chemoresistance to 5-fluorouracil. Despite its promise, we report that macrophage-specific overexpression of thymidine phosphorylase results in macrophage-induced chemoresistance to TAS-102 that is insensitive to tipiracil inhibition. Furthermore, we illustrate the human-specific nature of this mechanism, as mouse macrophages do not express substantial levels of thymidine phosphorylase, which constrains the applicability of mouse models. To study the importance of macrophages in chemoresistance to trifluridine, we developed a humanized mouse model with tumor-implanted human macrophages and demonstrated their important role in treatment resistance to pyrimidine analogs. Additionally, our findings revealed that macrophages represent a significant source of thymidine phosphorylase expression, comprising over 40 % of the expressing cells, in human colorectal cancer, thereby contributing to chemoresistance. •Resistance to pyrimidine analogs is a major concern in digestive cancers.•Macrophages appear to be as key player in chemoresistance.•Human macrophages express high levels of thymidine phosphorylase in tumors.•TP expression in human macrophages confers a resistance to TAS-102, a promising alternative to 5-FU.