CCR8-targeted specific depletion of clonally expanded Treg cells in tumor tissues evokes potent tumor immunity with long-lasting memory

Abstract

Foxp3-expressing CD25+CD4+ regulatory T cells (Tregs) are abundant in tumor tissues. Here, hypothesizing that tumor Tregs would clonally expand after they are activated by tumor-associated antigens to suppress antitumor immune responses, we performed single-cell analysis on tumor Tregs to characterize them by T cell receptor clonotype and gene-expression profiles. We found that multiclonal Tregs present in tumor tissues predominantly expressed the chemokine receptor CCR8. In mice and humans, CCR8+ Tregs constituted 30 to 80% of tumor Tregs in various cancers and less than 10% of Tregs in other tissues, whereas most tumor-infiltrating conventional T cells (Tconvs) were CCR8–. CCR8+ tumor Tregs were highly differentiated and functionally stable. Administration of cell-depleting anti-CCR8 monoclonal antibodies (mAbs) indeed selectively eliminated multiclonal tumor Tregs, leading to cure of established tumors in mice. The treatment resulted in the expansion of CD8+ effector Tconvs, including tumor antigen-specific ones, that were more activated and less exhausted than those induced by PD-1 immune checkpoint blockade. Anti-CCR8 mAb treatment also evoked strong secondary immune responses against the same tumor cell line inoculated several months after tumor eradication, indicating that elimination of tumor-reactive multiclonal Tregs was sufficient to induce memory-type tumor-specific effector Tconvs. Despite induction of such potent tumor immunity, anti-CCR8 mAb treatment elicited minimal autoimmunity in mice, contrasting with systemic Treg depletion, which eradicated tumors but induced severe autoimmune disease. Thus, specific removal of clonally expanding Tregs in tumor tissues for a limited period by cell-depleting anti-CCR8 mAb treatment can generate potent tumor immunity with long-lasting memory and without deleterious autoimmunity.

Keratinocyte-derived cytokine TSLP promotes growth and metastasis of melanoma by regulating the tumor-associated immune microenvironment

“…This suggests that MDSCs and S100A8/A9 may rather be downstream of GATA3 + Tregs. Nevertheless, the function of GATA3 + Tregs in melanomagenesis remains to be better defined using strategies to selectively deplete this Treg population — for example, by CCR8 antibody–mediated depletion as reported recently ( 56 ).…”

Therapeutic strategies for gastric cancer targeting immune cells: Future directions

“…T regs can migrate to TME under the action of chemokines such as CCR4-CCL17/22, CCR8-CCL1, CCR10-CCL28, and CXCR3-CCL9/10/11 ( 128 ), so blocking chemokines and chemokine receptors can inhibit T regs migration thus indirectly reduce T regs in the TME. Anti-CCR4 mAb and anti-CCR8 mAb have been shown to selectively deplete tumor-infiltrating T regs ( 138 , 139 ). In addition, the tyrosine kinase inhibitor imatinib can selectively induce T regs apoptosis by reducing the intensity of TCR signaling through the inhibition of lymphocyte-specific protein tyrosine kinase (LCK) ( 140 ).…”

Extracellular Vesicles and Their Roles in the Tumor Immune Microenvironment

“…Increased Treg/Tconv (conventional T cells) and Treg/CD8 + T cell ratios at the tumor site have often been described and are associated with poor prognosis in several cancers [ 127 ]. As the depletion of Treg cells significantly reduces tumor burden [ 128 , 129 , 130 ], strategies targeting receptors (CCR4, CD25, CTLA-4, CCR8) preferentially expressed on tumor infiltrating Tregs [ 125 , 128 , 131 ] are currently being evaluated in clinical trials.…”