Tumor-associated macrophage-derived chemokine CCL5 facilitates the progression and immunosuppressive tumor microenvironment of clear cell renal cell carcinoma

Background: Tumor-associated macrophages (TAMs) dominate the malignancy of cancers by perturbing the tumor microenvironment (TME). However, the clinical implications of heterogeneous subpopulations of TAMs in clear cell renal cell carcinoma (ccRCC) remain to be elucidated. Methods: We comprehensively evaluated the prognostic implications, biological behaviors, and immunogenomics features of the C-C Motif Chemokine Ligand 5 (CCL5) expression and CCL5(+) TME in vitro and in 932 real-world ccRCC patients from testing and public validation cohorts. Flow cytometry was used to examine the functional patterns of CCL5(+) TAMs with TME cell-infiltrating characterizations. Results: Our results identified distinct prognostic clusters with gradual changes in clinicopathological indicators based on CCL5 expression. Knockdown of CCL5 significantly restrained cell viability, migration capabilities of ccRCC cells, and the inhibits the proliferation and chemotaxis of THP1-derived TAMs. Mechanically, down-regulation of CCL5 arrested epithelial-mesenchymal transition by modulating the PI3K/AKT pathway in ccRCC cells. In ccRCC samples with CCL5 upregulation, the proportion of CCL5(+) TAMs and PD-L1(+) CD68(+) TAMs were prominently increased, showing a typical suppressive tumor immune microenvironment (TIME). Besides, intra-tumoral CCL5(+) TAMs showed distinct pro-tumorigenic TME features characterized by exhausted CD8(+) T cells and increased expression of immune checkpoints. Furthermore, elevated CCL5(+) TAMs infiltration was prominently associated with a dismal prognosis for patients with ccRCC. Conclusion: In conclusion, this study first revealed the predictive value of the chemokine CCL5 on the progression and TME of ccRCC. The intra-tumoral CCL5(+) TAMs could be applied to comprehensively evaluate the prognostic patterns as well as unique TME characteristics among individuals, allowing for the identification of immunophenotypes and promotion of treatment efficiency for ccRCC.