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

Abstract

The presence of T regulatory (Treg) cells in the tumor microenvironment is associated with poor prognosis and resistance to therapies aimed at reactivating anti-tumor immune responses. Therefore, depletion of tumor-infiltrating Tregs is a potential approach to overcome resistance to immunotherapy. However, identifying Treg-specific targets to drive such selective depletion is challenging. CCR8 has recently emerged as one of these potential targets. Here, we describe GS-1811, a novel therapeutic monoclonal antibody that specifically binds to human CCR8 and is designed to selectively deplete tumor-infiltrating Tregs. We validate previous findings showing restricted expression of CCR8 on tumor Tregs, and precisely quantify CCR8 receptor densities on tumor and normal tissue T cell subsets, demonstrating a window for selective depletion of Tregs in the tumor. Importantly, we show that GS-1811 depleting activity is limited to cells expressing CCR8 at levels comparable to tumor-infiltrating Tregs. Targeting CCR8 in mouse tumor models results in robust anti-tumor efficacy, which is dependent on Treg depleting activity, and synergizes with PD-1 inhibition to promote anti-tumor responses in PD-1 resistant models. Our data support clinical development of GS-1811 to target CCR8 in cancer and drive tumor Treg depletion in order to promote anti-tumor immunity.

Deconstructing Complexity: A Computational Topology Approach to Trajectory Inference in the Human Thymus withtviblindi

“…The RNA expression profile of Treg-atlas corresponds to the protein profile of End#6 suggesting that we are analyzing the same population (Figure 7D-F, compare to Figure 5B and Figure 6B, C). Apart from markers already presented in our mass cytometry panels, Treg-atlas show a sharp increase in IL-1R2 RNA (Figure 7E) further reinforcing the hypothesis that these cells are recirculating from the periphery ( 74,78–82 ). Furthermore, Figure 7G shows the expression of additional chemokine receptors known to play a role in guiding Treg cells to peripheral sites (tumors and other sites of inflammation).…”

SPARTIN: a Bayesian method for the quantification and characterization of cell type interactions in spatial pathology data

“…Most notably, mean logit-CTIP was most significantly negatively associated with CD244, a gene associated with increased cytotoxicity in natural killer cells ( Agresta et al, 2018 ). In addition, mean logit-CTIP was significantly negatively associated with expression of Cathepsin S, a gene associated with immunosuppression in the tumor microenvironment, and C-C motif chemokine receptor 8 (CCR8), a gene related to immunosuppressive T regulatory cells ( Fuchs et al, 2020 ; Weaver et al, 2022 ).…”

In situ analysis of CCR8 + regulatory T cells and cytotoxic CD8 + T cells in human lung squamous cell carcinoma: biological insights and clinical implications

“…CCR8 + Tregs have recently attracted attention as immunosuppressive cells that are highly concentrated in malignant tumor tissues compared with in peripheral blood and normal tissues in both humans and mice [19][20][21][22]. Using ow cytometry and public mRNA database analysis, our previous study showed high CCR8 + Treg in ltration within tumors that was associated with poor prognosis in lung cancer patients [16].…”

“…Our previous study also reported that CCR8 + Tregs are involved in the tumor immunosuppressive microenvironment in lung cancer, including LSCC [16]. Furthermore, preclinical studies in several murine tumor models, including lung carcinoma, have demonstrated that depletion of CCR8 + Tregs by anti-CCR8 antibody administration resulted in a marked anti-tumor effect [16][17][18][19][20][21][22]. Their mechanism of action has been suggested to be via enhancement of CD8 + T cell function, as evidenced by increased expression levels of granzyme B (GzmB) and interferon-γ in CD8 + T cells following antibody administration and abolished in vivo e cacy from CD8 + T cell depletion [17,18].…”