Abstract 4874: Anti-CCR8 mediates long-lasting antitumor immunological memory and enhances anti-tumor immunity in immune-cold cancer through the combination with chemotherapy

Abstract Tumor infiltrating regulatory T cells (Tregs) suppress CD8+ T cells and facilitate tumor progression. Tumor Tregs are elevated in a variety of malignancies and have been associated with poor prognosis. Targeting Tregs presents an appealing strategy in cancer immunotherapy. Recent research has identified the chemokine receptor CCR8 is preferentially expressed by tumor Tregs and labels highly suppressive Tregs. Thus, using anti-CCR8 mAb to deplete tumor Tregs could be an efficient and safe strategy that is widely being explored. Although the anti-tumor efficacy of CCR8 mAb was reported, the dynamics and specific contributions of Tregs and CD8+ T cells to anti-tumor activity are still not fully elucidated. We found that tumor Tregs were rapidly depleted within two days, and CD8+ T cells increased after one week following treatment with anti-CCR8 in both the MC38 and CT26 tumor models, which coincided with the observed tumor growth inhibition. Tumor volume was found to have a strong negative correlation with the percentage of tumor-infiltrating CD8+ T cells, suggesting that the increased tumor CD8+ T cells may be indicative of an active anti-tumor immune response. Furthermore, treatment with CCR8 mAb has shown dose-dependent efficacy in controlling the growth of CT26 tumor. In the 1 mg/kg dosage group, 3 out of 10 mice exhibited a complete response (CR), while in the 3 mg/kg dosage group, 4 out of 10 mice achieved a CR. Rechallenging the mice with 50-fold more tumor cells on the contralateral side of the CR mice resulted in the expulsion of tumor growth without any treatment, suggesting that the use of CCR8 mAb induces a long-lasting antitumor immunological memory. This is crucial for maintaining persistent tumor immune surveillance and achieving durable responses to cancer therapy. This finding underscores the potential of CCR8 mAb not only in directly targeting tumor growth but also in bolstering the host's immune memory, contributing to a more comprehensive and enduring antitumor defense. In addition, further improved tumor growth inhibition was observed when combining anti-CCR8 with docetaxel, oxaliplatin, or gemcitabine in immune cold tumor models. PD analysis revealed that the combination of CCR8 mAb therapy with gemcitabine induced the depletion of Tregs, increase of CD8+ T cells, decrease of tumor-associated macrophages, and the activation of DCs, which are instrumental in treating immune-cold tumors. This suggests that the combined therapy may enhance the antitumor immune response by modulating the tumor microenvironment, thereby improving the efficacy of cancer treatment. Collectively, these findings advance our understanding of CCR8 as a promising target for Treg depletion in anti-cancer drug development and therapy. Citation Format: Shuiqing Hu, Minjuan Deng, Wei Tan, Rui Liu, Amin Zhang, Lu Tan, Mengqian Chen, Pu Sun, Li Luo, Wen Li, Juan Yang, Jiyuan Zhang, Wei Jin, Zhirong Shen. Anti-CCR8 mediates long-lasting antitumor immunological memory and enhances anti-tumor immunity in immune-cold cancer through the combination with chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4874.