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

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, in the current study, we report that macrophage-specific overexpression of thymidine phosphorylase results in macrophage-induced chemoresistance to TAS-102 that is insensitive to tipiracil inhibition. In addition, we demonstrate the human specificity of this mechanism, as mouse macrophages do not express significant levels of thymidine phosphorylase. 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. We also showed in human colorectal cancer that macrophages represent a major source of thymidine phosphorylase expression leading to chemoresistance. Significance Thymidine phosphorylase overexpression in TAMs confers chemoresistance to TAS-102 in digestive cancers.