The impact of CCR8+ regulatory T cells on cytotoxic T cell function in human lung cancer

• Published in: Scientific reports Vol. 12; no. 1; pp. 5377 - 12
• Main Authors: Haruna, Miya, Ueyama, Azumi, Yamamoto, Yoko, Hirata, Michinari, Goto, Kumiko, Yoshida, Hiroshi, Higuchi, Naoko, Yoshida, Tetsuya, Kidani, Yujiro, Nakamura, Yamami, Nagira, Morio, Kawashima, Atsunari, Iwahori, Kota, Shintani, Yasushi, Ohkura, Naganari, Wada, Hisashi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 30.03.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 631/250; 631/250/251; 692/4028/67/1612; 692/4028/67/580; Animal models; Animals; Cancer immunotherapy; Cancer therapies; CCR8 protein; CD8 antigen; Cell culture; Cytotoxicity; Genomes; Homeostasis; Humanities and Social Sciences; Humans; Immune checkpoint inhibitors; Immune response; Immune Tolerance; Immunoregulation; Immunosuppression; Immunotherapy; Lung cancer; Lung Neoplasms - pathology; Lymphocytes; Lymphocytes T; Metastases; Mice; multidisciplinary; Patients; Receptors, CCR8 - metabolism; Science; Science (multidisciplinary); T-Lymphocytes, Cytotoxic; T-Lymphocytes, Regulatory; Tumor-infiltrating lymphocytes; Tumors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-022-09458-5

Regulatory T cells (Tregs) suppress the host immune response and maintain immune homeostasis. Tregs also promote cancer progression and are involved in resistance to immune checkpoint inhibitor treatments. Recent studies identified selective CCR8 expression on tumor-infiltrating Tregs; CCR8+ Tregs have been indicated as a possible new target of cancer immunotherapy. Here, we investigated the features of CCR8+ Tregs in lung cancer patients. CCR8+ Tregs were highly activated and infiltration of CCR8+ Tregs in tumors was associated with poor prognosis in lung cancer patients. We also investigated their immune suppressive function, especially the influence on cytotoxic T lymphocyte cell function. The Cancer Genome Atlas analysis revealed that CD8 T cell activities were suppressed in high CCR8-expressing tumors. Additionally, depletion of CCR8+ cells enhanced CD8 T cell function in an ex vivo culture of lung tumor-infiltrating cells. Moreover, CCR8+ Tregs, but not CCR8− Tregs, induced from human PBMCs markedly suppressed CD8 T cell cytotoxicity. Finally, we demonstrated the therapeutic effect of targeting CCR8 in a murine model of lung cancer. These findings reveal the significance of CCR8+ Tregs for immunosuppression in lung cancer, especially via cytotoxic T lymphocyte cell suppression, and suggest the potential value of CCR8-targeted therapy for cancer treatment.