CCL5-deficiency Enhances Intratumoral Infiltration Of CD8~+ T Cells In Colorectal Cancer

Purpose:Colorectal cancer（CRC）shows resistance to several immunotherapies.The absence of CD8⁺T cells in the central tumor area has become a major obstacle for solid tumor immunotherapy.Thus,novel therapeutic strategies that could promote CD8⁺T cells to accumulate in the central tumor area are urgently needed.Experimental Design:The impacts of CCL5-deficiency on tumor growth and metastasis were evaluated in CRC mouse models.Intratumoral infiltration of CD8⁺T cells induced by CCL5-deficiency was determined by immunofluorescence staining and flow cytometry.RNA-sequencing,in vitro co-culture system and hypoxia measurements were used to figure out the mechanism on how CCL5 modulates the phenotype of TAMs to affect the CD8⁺T cells migration.Finally,these results gotten from mouse models were verified by immunohistochemically staining of clinical samples of CRC patients.Results:CCL5-deficiency delayed tumor growth and metastasis via facilitating CD8⁺T cells to accumulate into tumor sites in CRC mouse models.Furthermore,CCL5-deficiency could reduce the resistance to anti-PD-1 antibody therapy in CRC mouse model.Mechanically,knock-down of CCL5 could result in the metabolic disorders in CD11b^hiF4/80^low TAMs and suppress the expression of S100a9 to promote the migration of CD8⁺T cells in the tumor microenvironment.These findings were also verified by the data of clinical samples from CRC patients.Conclusions:These data provide evidence that CCL5-deficiency can enhance CD8⁺T cells to infiltrate into central tumor area via modulating the activity of CD11b^hiF4/80^lowow TAMs in CRC.