Ccr8, the CC chemokine receptor 8, is a key molecule involved in immune cell regulation. It is expressed on certain immune cell subsets, and its ligands are CC-motif chemokines. Ccr8-mediated signaling may be involved in cell migration and immune response-related pathways, playing an important role in the immune system [4].

Multiple studies have explored the role of Ccr8 in the context of tumors. In mouse models of non-small cell lung carcinoma (NSCLC), single-cell RNA-sequencing identified a tumor-infiltrating regulatory T cell (Treg) population uniquely expressing Ccr8 along with Treg activation markers [1]. Depletion of Ccr8+ Tregs in mouse tumor models, either through an Fc-optimized anti-CCR8 antibody or other cell-depleting anti-CCR8 monoclonal antibodies, led to effective antitumor immunity. This was often accompanied by the expansion of CD8+ effector T cells, and in some cases, synergized with anti-PD-1 therapy. The depletion was tumor-Treg-restricted, sparing CCR8+ T cells in other tissues [1,2,3,6,7]. In a glioblastoma mouse model, lactate accumulation upregulated Ccr8 expression, and inhibiting lactate generation reduced tumor-infiltrating CCR8+ Tregs, enhancing CAR-T therapy efficacy [5].

In conclusion, Ccr8 is a crucial regulator in the immune response, especially in the tumor microenvironment. Studies using mouse models have revealed that targeting Ccr8 for the depletion of tumor-infiltrating Tregs can evoke potent antitumor immunity with long-lasting memory and without severe autoimmunity, suggesting its potential as a therapeutic target for cancer immunotherapy [1,2,3,6,7,8,9].

References:

1. Van Damme, Helena, Dombrecht, Bruno, Kiss, Máté, Laoui, Damya, Van Ginderachter, Jo Agnes. . Therapeutic depletion of CCR8+ tumor-infiltrating regulatory T cells elicits antitumor immunity and synergizes with anti-PD-1 therapy. In Journal for immunotherapy of cancer, 9, . doi:10.1136/jitc-2020-001749. https://pubmed.ncbi.nlm.nih.gov/33589525/

2. Campbell, Joseph R, McDonald, Bryan R, Mesko, Paul B, Jain, Renu, Lan, Ruth Y. 2021. Fc-Optimized Anti-CCR8 Antibody Depletes Regulatory T Cells in Human Tumor Models. In Cancer research, 81, 2983-2994. doi:10.1158/0008-5472.CAN-20-3585. https://pubmed.ncbi.nlm.nih.gov/33757978/

3. Kidani, Yujiro, Nogami, Wataru, Yasumizu, Yoshiaki, Ohkura, Naganari, Sakaguchi, Shimon. . CCR8-targeted specific depletion of clonally expanded Treg cells in tumor tissues evokes potent tumor immunity with long-lasting memory. In Proceedings of the National Academy of Sciences of the United States of America, 119, . doi:10.1073/pnas.2114282119. https://pubmed.ncbi.nlm.nih.gov/35140181/

4. Korbecki, Jan, Grochans, Szymon, Gutowska, Izabela, Barczak, Katarzyna, Baranowska-Bosiacka, Irena. 2020. CC Chemokines in a Tumor: A Review of Pro-Cancer and Anti-Cancer Properties of Receptors CCR5, CCR6, CCR7, CCR8, CCR9, and CCR10 Ligands. In International journal of molecular sciences, 21, . doi:10.3390/ijms21207619. https://pubmed.ncbi.nlm.nih.gov/33076281/

5. Sun, Ting, Liu, Bin, Li, Yanyan, Yu, Dingjia, Yang, Wei. 2023. Oxamate enhances the efficacy of CAR-T therapy against glioblastoma via suppressing ectonucleotidases and CCR8 lactylation. In Journal of experimental & clinical cancer research : CR, 42, 253. doi:10.1186/s13046-023-02815-w. https://pubmed.ncbi.nlm.nih.gov/37770937/

6. Nagira, Yoji, Nagira, Morio, Nagai, Ryohei, Wada, Hisashi, Tanaka, Hidekazu. . S-531011, a Novel Anti-Human CCR8 Antibody, Induces Potent Antitumor Responses through Depletion of Tumor-Infiltrating CCR8-Expressing Regulatory T Cells. In Molecular cancer therapeutics, 22, 1063-1072. doi:10.1158/1535-7163.MCT-22-0570. https://pubmed.ncbi.nlm.nih.gov/37420296/

7. Weaver, Jessica D, Stack, Edward C, Buggé, Joshua A, Depis, Fabien, Gostissa, Monica. 2022. Differential expression of CCR8 in tumors versus normal tissue allows specific depletion of tumor-infiltrating T regulatory cells by GS-1811, a novel Fc-optimized anti-CCR8 antibody. In Oncoimmunology, 11, 2141007. doi:10.1080/2162402X.2022.2141007. https://pubmed.ncbi.nlm.nih.gov/36352891/

8. Wen, Yuanjia, Xia, Yu, Yang, Xiangping, Li, Huayi, Gao, Qinglei. 2025. CCR8: a promising therapeutic target against tumor-infiltrating regulatory T cells. In Trends in immunology, 46, 153-165. doi:10.1016/j.it.2025.01.001. https://pubmed.ncbi.nlm.nih.gov/39890548/

9. Moser, Bernhard. 2022. Chemokine Receptor-Targeted Therapies: Special Case for CCR8. In Cancers, 14, . doi:10.3390/cancers14030511. https://pubmed.ncbi.nlm.nih.gov/35158783/