Combined administration of interleukin-2 and 18 with anti-PD-L1 antibody induces CCL5-positive CD8 T cells to suppress liver tumors.

Remarkable progress has been made in cancer immunotherapy, partly because of the development of immune checkpoint inhibitors. However, their efficacy varies across cancer types, with limited response observed in solid tumors, such as hepatocellular carcinoma (HCC). The primary cause of this low efficacy is insufficient infiltration of effector cells, such as cytotoxic CD8+ T cells, into the tumor tissue. This study investigated whether recombinant interleukin (rIL)-2, rIL-18, and antiprogrammed cell death-ligand 1 (αPD-L1) antibody (Ab) could serve as novel immunotherapies for HCC. Multidrug resistance gene 2-deficient mice, a spontaneously occurring liver cancer model associated with aging, were administered rIL-2, rIL-18, and αPD-L1Ab. Antitumor effects were evaluated using computed tomography and serum alpha-fetoprotein levels. Significant tumor shrinkage was observed in the rIL-2+rIL-18+αPD-L1Ab group, but not in the rIL-2+αPD-L1Ab or rIL-18+αPD-L1Ab groups. Concurrent administration of αCD8-neutralizing antibody abolished the antitumor effect, indicating CD8+ T-cell dependency. Spatial gene expression profiling revealed that intratumoral CD8+ effector T cells express and secrete CCL5 after treatment, promoting CD8+ T-cell mobilization to the liver and enhancing antitumor efficacy. Pretreatment with a CCL5 neutralizing antibody suppressed CD8+ cell infiltration into the tumor, eliminating the antitumor effect. The triple combination therapy used in this study promotes the infiltration and maintenance of CD8+ T cells in the liver, suggesting a promising new immunotherapy for HCC.