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We aimed to characterize the molecular features associated with\n                      <jats:italic>CCR5<\/jats:italic>\n                      \/\n                      <jats:italic>CCL5<\/jats:italic>\n                      expression in CRC and to determine whether\n                      <jats:italic>CCR5<\/jats:italic>\n                      \/\n                      <jats:italic>CCL5<\/jats:italic>\n                      levels could impact treatment outcomes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      7604 CRCs tested with NextGen Sequencing on DNA and RNA were analyzed. Molecular features were evaluated according to\n                      <jats:italic>CCR5<\/jats:italic>\n                      and\n                      <jats:italic>CCL5<\/jats:italic>\n                      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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      <jats:italic>CCR5<\/jats:italic>\n                      \/\n                      <jats:italic>CCL5<\/jats:italic>\n                      expression was higher in right-sided versus left-sided tumors, and positively associated with consensus molecular subtypes 1 and 4. Higher\n                      <jats:italic>CCR5<\/jats:italic>\n                      \/\n                      <jats:italic>CCL5<\/jats:italic>\n                      expression was associated with higher tumor mutational burden, deficiency in mismatch repair and programmed cell death ligand 1 (PD-L1) levels. Additionally, high\n                      <jats:italic>CCR5<\/jats:italic>\n                      \/\n                      <jats:italic>CCL5<\/jats:italic>\n                      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 downregulated. Low\n                      <jats:italic>CCR5<\/jats:italic>\n                      \/\n                      <jats:italic>CCL5<\/jats:italic>\n                      expression was associated with increased benefit from cetuximab-FOLFOX treatment in the CALGB\/SWOG 80405 trial, where significant treatment interaction was observed with biologic agents and chemotherapy backbone.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Our data show a strong association between\n                      <jats:italic>CCR5\/CCL5<\/jats:italic>\n                      gene expression and distinct molecular features, gene expression profiles, TME cell infiltration, and treatment benefit in CRC. Targeting the CCR5\/CCL5 axis may have clinical applications in selected CRC subgroups and may play a key role in developing and deploying strategies to modulate the immune TME for CRC treatment.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2023-007939","type":"journal-article","created":{"date-parts":[[2024,1,11]],"date-time":"2024-01-11T21:55:15Z","timestamp":1705010115000},"page":"e007939","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":25,"title":["<i>CCR5<\/i>\n                    and\n                    <i>CCL5<\/i>\n                    gene expression in colorectal cancer: comprehensive profiling and clinical 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