Tumor-derived CCL5 recruits CCR1+ macrophages to suppress apoptosis and drive proliferation in duodenal adenocarcinoma.

Abstract

Duodenal adenocarcinoma (DA) is a rare gastrointestinal malignancy associated with poor prognosis and limited therapeutic options. To define the DA tumor microenvironment (TME), we performed single-cell RNA sequencing (scRNA-seq) on primary DA tumors and matched adjacent normal tissues. This analysis revealed substantial heterogeneity among malignant epithelial cells, including a transcriptionally distinct subset characterized by the upregulation of immune-related genes, which constitutes an immune-associated transcriptional program. Notably, this program included high expression of the chemokine CCL5, which facilitated the recruitment of CCR1⁺ macrophages. Using patient-derived DA organoids, we identified malignant cells exhibiting immune-related transcriptional signatures, including elevated CCL5. Functional assays demonstrated that CCL5 promoted CCR1⁺ macrophage migration, an effect suppressed by both the CCR1 antagonist BX471 and CCL5-neutralizing antibody. In co-culture, CCL5-expressing DA organoids displayed enhanced survival and proliferation in the presence of CCR1⁺ macrophages, while pharmacological blockade of CCR1 significantly increased tumor cell death. Bulk transcriptomic profiling revealed that CCR1 downregulates pro-apoptotic signaling in tumor cells, thereby promoting cell survival and growth. Importantly, combining CCL5/CCR1 inhibitors with standard chemotherapeutic agents resulted in synergistic tumor cell killing. Together, our findings establish the CCL5/CCR1 axis as a key mediator of tumor-macrophage crosstalk in DA, supporting immune evasion and chemoresistance via suppression of macrophage-induced apoptosis. Targeting this axis may represent a promising therapeutic strategy to enhance the efficacy of conventional chemotherapy in DA.