How Does CCR8+Treg Targeted Therapy Overcome PD1 Resistance?
Recently, Journal of Thoracic Oncology (IF 20.8) published a groundbreaking study on lung cancer immunotherapy titled "Selective Depletion of CCR8+Treg Cells Enhances the Antitumor Immunity of Cytotoxic T Cells in Lung Cancer by Dendritic Cells". This study uncovers a novel regulatory mechanism of antitumor immunity mediated by the "CCR8⁺Treg-CCL5⁺DC-CD8⁺T cell axis" and verifies the significant efficacy of the combination therapy of CCR8 antibody and PD1 inhibitor. Multiple products from Absin were utilized in the study.
I. Research Background: Why Focus on "CCR8⁺Treg"?
In the immunotherapy of non-small cell lung cancer (NSCLC), tumor-infiltrating regulatory T cells (Treg) are the core "culprit" leading to PD1 inhibitor resistance. They suppress antitumor immunity by secreting inhibitory cytokines and directly killing effector T cells. However, traditional Treg depletion therapies are prone to inducing systemic autoimmune reactions. Therefore, specific targeting of Treg subsets within the tumor microenvironment (TME) has become a research focus.
The research team found that CCR8 (C-C chemokine receptor 8) is highly expressed only in tumor-infiltrating Treg, while its expression is low in Treg from peripheral blood and spleen (Figures 1A and 1B in the original article). This makes CCR8 an ideal target for "precisely depleting intratumoral Treg without disrupting systemic immune homeostasis". Although previous studies have confirmed the antitumor potential of CCR8 inhibitors, the specific mechanism of action—especially the interaction with dendritic cells (DC) and cytotoxic CD8⁺T cells—remained unclear. This was exactly the core scientific question addressed in this study.
II. Core Research Approach: A "Three-Step" Strategy to Analyze Mechanism and Efficacy
Following the classic scientific research logic of "clinical problem → animal model verification → mechanism analysis → clinical translation", the research team revealed the regulatory role of CCR8⁺Treg through three steps:
Step 1: Verify the Correlation Between CCR8⁺Treg and Immune Resistance
Using public datasets (GSE99254, GSE81089) and clinical samples, the team found that the proportion of CCR8⁺Treg in NSCLC tumors was significantly higher than that in normal tissues, and the abundance of CCR8⁺Treg was positively correlated with PD1 inhibitor resistance.
Step 2: Verify the Synergistic Efficacy of "CCR8 Antibody + PD1 Inhibitor" in Animal Models
Four mouse models of NSCLC (LLC, KL, KP-1, KP-2) were established. The combination therapy was found to significantly inhibit tumor growth (especially in PD1-resistant models) without toxic side effects such as weight loss or cytokine storm.
Step 3: Analyze the Molecular Mechanism—Identifying the "CCR8⁺Treg-CCL5⁺DC-CD8⁺T Axis"
Through experiments including single-cell sequencing (scRNA-seq, scTCR-seq), flow cytometry, and in vitro co-culture, the team confirmed that CCR8⁺Treg inhibits DC from secreting IL-12 through direct interaction with CCL5⁺DC. After depletion of CCR8⁺Treg, CCL5⁺DC can activate the JAK-STAT pathway and enhance the cytotoxicity of CD8⁺T cells.
III. Key Scientific Progress: 4 Breakthroughs Updating the Understanding of Lung Cancer Immunology
1. First Proposal of the "CCR8⁺Treg-CCL5⁺DC-CD8⁺T Axis" Regulatory Model
The study found that intratumoral CCL5⁺DC highly express CCR8 ligands (CCL1, CCL8), which can specifically bind to CCR8⁺Treg and inhibit DC from secreting IL-12. After depleting Treg with CCR8 antibody, CCL5⁺DC are activated via the JAK-STAT pathway, secrete large amounts of IL-12, and further enhance the Granzyme B expression and proliferation ability of CD8⁺T cells.
2. Combination Therapy Can "Remodel TME" and Reverse Immune Suppression
Single-cell sequencing showed that after combination therapy, "antitumor cells" (activated NK cells, CCL5⁺DC, proliferative CD8⁺T cells, Th17 cells) in TME increased significantly, while "pro-tumor cells" (CCR8⁺Treg, S100A9⁺monocytes) decreased significantly.
3. Induce Long-Term Immune Memory to Prevent Tumor Recurrence
In the KP-2 model, mice that achieved complete remission after combination therapy showed no recurrence after re-inoculation with tumor cells. Flow cytometry analysis revealed a significant increase in the proportions of CD8⁺central memory T cells (Tcm) and effector memory T cells (Tem) in their peripheral blood.
4. Significant Potential for Clinical Translation
Preliminary clinical data showed that in advanced NSCLC patients treated with CCR8 antibody (LM108) combined with PD1 inhibitor (Toripalimab), one patient with squamous cell carcinoma achieved partial remission (PR) with no progression for half a year. Meanwhile, it was found that molecules such as PGF and CCL4 in pre-treatment plasma may serve as efficacy prediction markers.
IV. Absin Products: The "Unsung Heroes" Supporting Key Experiments
In the core experiments of this study, including cell culture, cytokine detection, and flow cytometry verification, multiple reagents from Absin played important roles, ensuring the stability and reliability of the experimental results. The specific products and application scenarios are as follows:
1. Cell Culture Products: Providing "Basic Support" for Cell Experiments
|
Product Name |
Product Code |
Application Scenario |
Role in the Study |
|
CellXViva Mouse T cell Activation Kit |
Culture of mouse LLC, KL, KP-1, KP-2 cancer cell lines and DC2.4 cells |
Provides nutrients required for cell growth, maintains cell viability and normal functions, and serves as the basis for subsequent tumor inoculation and in vitro co-culture experiments |
2. Cytokine Detection Products: Accurately Quantifying "Immune Regulatory Signals"
|
Product Name |
Product Code |
Application Scenario |
Role in the Study |
|
Mouse IL-10 ELISA Kit |
Detection of IL-10 in supernatant of in vitro Treg-DC co-culture |
Verifies whether the inhibitory effect of CCR8⁺Treg on DC is dependent on IL-10 (results showed no significant difference, excluding this pathway) |
|
|
Human/Mouse/Rat TGF-β1 ELISA Kit |
Detection of TGF-β in supernatants of in vitro Treg-DC and Treg-CD8⁺T co-cultures |
Similarly excludes the TGF-β-mediated inhibitory pathway, confirming that the inhibition of DC by CCR8⁺Treg is "cell-contact dependent" |
|
|
LLC lung cancer mouse tumor antigen-specific T cell content detection stimulation kit |
Detection of tumor-infiltrating antigen-specific CD8⁺T cells |
Directly verifies that the proportion of LLC antigen-specific CD8⁺T cells in tumors increases after combination therapy, confirming the "antigen-specific antitumor effect" of the therapy |
This study not only uncovers a novel mechanism by which CCR8⁺Treg regulates lung cancer immunity but also provides a potential therapeutic option of "CCR8 antibody + PD1 inhibitor" for patients with PD1 resistance. As a supplier of scientific research reagents, Absin has always adhered to the goal of "supporting scientific research breakthroughs with high-quality reagents". The participation and support of multiple Absin products in this study are a recognition of the quality of our products.
Absin will provide more comprehensive reagent solutions (such as flow cytometry antibodies, cytokines, detection kits, etc.) to support the scientific research work of researchers.
References:
Selective Depletion of CCR8+ Treg Cells Enhances the Antitumor Immunity of Cytotoxic T Cells in Lung Cancer by Dendritic Cells. J Thorac Oncol. 2025 Mar 6.
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