CCR8 expression

Mechanistically, metformin reduces histone acetylation at the CCR8 promotor and inhibits CCR8 expression by upregulating AMP-activated protein kinase (AMPK)-activated sirtuin 2 (SIRT2). Metformin enhances the effectiveness of anti-PD-1 immunotherapy by reducing CCR8 expression on tumor-infiltrating Treg cells, suggesting that metformin has an antitumor effect by alleviating immunosuppression and promoting T cell-mediated immune response.

Finally, we identified that TNFR2+CCR8+ Tregs but not total Tregs are positively correlated with adverse prognosis in CRC and gastric cancer. Our work reveals the regulatory mechanisms of CCR8 in Tregs and identifies TNFR2 as a promising target for immunotherapy.

Utilizing lactate generation inhibitor not only reprogramed glucose metabolism of cancer stem cells, but also alleviated immunosuppression of tumor microenvironment and reduced tumor-infiltrating CAR-Treg cells, which may be a potential strategy to enhance CAR-T function in glioblastoma therapy.

Molecular epidemiology studies highlight HNSCC as a tumor type with a high prevalence of CCR8+ itTregs to evaluate the anti-tumor activity of an anti-CCR8 antibody. CHS-114 (SRF114) is currently being evaluated in a Phase 1 clinical trial (NCT05635643).

P1a/1b, N=318, Recruiting, BeiGene | Not yet recruiting --> Recruiting

P1a/1b, N=318, Not yet recruiting, BeiGene

We have developed a human IgG1 antibody to preferentially eliminate CCR8-expressing Treg cells in tumor microenvironment through ADCC. The preclinical PK/PD findings and the methods used for translation to the clinic, including the selection of First-in-Human (FiH) dose, to inform the Phase I study design will be presented.

In addition, anti-CCR8 blocking downregulated IL10 expression produced by CD4 Tregs, and reversed the suppression by Tregs on the secretion and proliferation of CD8 T cells. CCR8 molecule could be a prognostic biomarker for GC cases and a therapeutic target for immune treatments.

Our findings suggest that higher levels of LAG3 in UM with histopathologically high-risk parameters predict high metastatic potential and that it could be used as a targeted immunotherapy alone or in combination with PD-1/PD-L1 blockade agents.

Conclusions Our preclinical data demonstrate high therapeutic potential of combining anti-CCR8 depleting antibody with radiotherapy to trigger synergistic enhancement of immune response in tumors that are refractory to immune checkpoint blockade. In conclusion, targeting CCR8-expressing TITRs in combination with radiotherapy displayed superior anti-tumor activity and prolonged survival than single-agent treatment alone.