CCR5 and CCL5 gene expression in colorectal cancer: comprehensive profiling and clinical value

作者：Francesca Battaglin, Yasmine Baca, Joshua Millstein, Yan Yang, Joanne Xiu, Hiroyuki Arai, Jingyuan Wang, Fang‐Shu Ou, Federico Innocenti, Shannon M. Mumenthaler, Priya Jayachandran, Natsuko Kawanishi, Annika Lenz, Shivani Soni, Sandra Algaze, Wu Zhang, Taline Khoukaz, Evanthia T. Roussos Torres, Andreas Seeber, Jim Abraham, Emil Lou, Philip A. Philip, Benjamin A. Weinberg, Anthony F. Shields, Richard M. Goldberg, John L. Marshall, Alan P. Venook, W. Michael Korn, Heinz‐Josef Lenz · 发表于：Journal for ImmunoTherapy of Cancer · 年份：2024 · DOI：10.1136/jitc-2023-007939 · 被引用次数：16 · 研究领域：Cancer Immunotherapy and Biomarkers、Colorectal Cancer Treatments and Studies、Cancer Mechanisms and Therapy

Background The C-C motif chemokine receptor 5 (CCR5)/C-C motif chemokine ligand 5 (CCL5) axis plays a major role in colorectal cancer (CRC). We aimed to characterize the molecular features associated with CCR5 / CCL5 expression in CRC and to determine whether CCR5 / CCL5 levels could impact treatment outcomes. Methods 7604 CRCs tested with NextGen Sequencing on DNA and RNA were analyzed. Molecular features were evaluated according to CCR5 and CCL5 tumor gene expression quartiles. The impact on treatment outcomes was assessed in two cohorts, including 6341 real-world patients and 429 patients from the Cancer and Leukemia Group B (CALGB)/SWOG 80405 trial. Results CCR5 / CCL5 expression was higher in right-sided versus left-sided tumors, and positively associated with consensus molecular subtypes 1 and 4. Higher CCR5 / CCL5 expression was associated with higher tumor mutational burden, deficiency in mismatch repair and programmed cell death ligand 1 (PD-L1) levels. Additionally, high CCR5 / CCL5 were associated with higher immune cell infiltration in the tumor microenvironment (TME) of MMR proficient tumors. Ingenuity pathway analysis revealed upregulation of the programmed cell death protein 1 (PD-1)/PD-L1 cancer immunotherapy pathway, phosphatase and tensin homolog (PTEN) and peroxisome proliferator-activated receptors (PPAR) signaling, and cytotoxic T-lymphocyte antigen 4 (CTLA-4) signaling in cytotoxic T lymphocytes, whereas several inflammation-related pathways were downreg...