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

No abstract available

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.

Importantly, anti-CCR8 CAR T cells exhibited antitumor effects on ATLL- and other CCR8-expressing T-ALL cells in vitro and in vivo, and prolonged the survival of ATLL and Jurkat tumor-bearing mouse models. In conclusion, these collective results show that anti-CCR8 CAR T cells possess strong antitumor activity and represent a promising therapeutic approach for ATLL and CCR8 tumors.

In addition, we found that CMab-2 and recCMab-2 recognized endogenous mCCR8 in P388 (a mouse lymphocyte-like cell line) and J774-1 cells (a mouse macrophage-like cell line). These data demonstrate that CMab-2 and recCMab-2 are useful for immunocytochemical analysis.

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.

To conclude, LM-108 is a novel Fc-optimized CCR8 antibody that selectively depletes tumor infiltrating Tregs thereby improving anti-tumor immune response either as monotherapy or combination therapy. Thus, LM-108 can be a promising therapeutic approach to overcome ICI resistance in cancer patients.

We are currently exploring the significance of these distinct populations and the impact of ZL-1218-mediated depletion of both CCR8 high- and CCR8 low-expressing subsets in multiple indications. Together, these data support the advancement of ZL-1218 into clinical evaluation as a novel therapeutic candidate to treat human solid tumors.

On the other hand, S-531011 didn’t reduce Tregs in human PBMC. Conclusions S-531011 is a promising drug which has a strong antitumor effect by depleting tumor-infiltrating CCR8+ Tregs, as a not only monotherapy but also combination therapy with other immune checkpoint inhibitors.

Finally, we evaluated the presence of CCR8 ligand in OSCC and observed increased chemokine CCL18, which was also able to upregulate CCR8 in activated Th cells. Overall, our data showed the immunomodulatory changes induced by the TME involving CCR8 expression and regulatory Th2 phenotypes, which are associated with PGE2 mediated VitD signaling pathway and CCL18 expression in OSCC.

Consistently, we observed minimal impact of systemic CCR8 ablation on the frequency, phenotype and function of tumour-infiltrating Treg cells and conventional T (Tconv) function. These findings suggest that CCR8 is not required for Treg cell accumulation and immunosuppressive function within tumours and that depletion of CCR8 Treg cells rather than blockade of CCR8 function is a more promising avenue for selective immunotherapy.

The human CCR8 protein were successfully detected in tumor-infiltrating Tregs in B-hCCR8 mice bearing MC38 tumor, but not in Treg cells from spleen. An anti-tumor efficacy study showed significant tumor growth inhibition of hCCR8 antibodies in B-hCCR8 mice bearing MC38 tumors, suggesting that the B-hCCR8 mouse model is an effective tool for in vivo efficacy evaluation of therapeutic hCCR8 antibodies to support anti-human CCR8 antibody clinical development.

Collectively, our findings highlight the efficacy and safety of targeting CCR8 for the depletion of tumor-promoting ti-Tregs in combination with anti-PD-1 therapy.