How Does CCR8+Treg Targeted Therapy Overcome PD1 Resistance?

Hits:35   Date: 9/22/2025

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	abs9468	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	abs520005	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	abs552208	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	abs57004	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.
 
Related Products:

Cell Culture
 

Product Name	Product Code	Application Scenario
AO/PI Double Staining	abs972	500mL

 
ELISA Kits
 

Product Code	Product Name	Application Scenario
abs510001	Human IL-2 ELISA Kit	96T
abs510002	Human IL-1β ELISA Kit	96T
abs510003	Human IL-6 ELISA Kit	96T
abs510005	Human IL-10 ELISA Kit	96T
abs510006	Human TNF-α ELISA Kit	96T
abs510008	Human VEGF ELISA Kit	96T
abs520001	Mouse IL-1β ELISA Kit  No reviews	96T
abs520003	Mouse IL-4 ELISA Kit	96T
abs520004	Mouse IL-6 ELISA Kit	96T
abs520005	Mouse IL-10 ELISA Kit	96T
abs520008	Mouse VEGF ELISA Kit	96T

T Cell Content Detection Stimulation Kits
 

Product Code	Product Name	Application Scenario
abs57001	B16F10 melanoma mouse tumor antigen-specific T cell content detection stimulation kit	20T/100T
abs57007	MC38 tumor antigen-specific T cell content detection stimulation kit for colorectal cancer mice	20T/100T
abs57010	Pan02 Pancreatic Cancer Mouse Tumor Antigen-specific T Cell Content Detection Stimulation Kit	20T/100T
abs57012	KPC pancreatic cancer mouse tumor antigen-specific T cell content detection stimulation kit	20T/100T
abs57014	GL261 mice brain tumor antigen specific T cells content test stimulus kit	20T/100T
abs57015	4T1 Breast Cancer Tumor Antigen Specific T Cells in Mice Content Test Stimulus Kit	20T/100T
abs57018	E0771 Breast Tumor Antigen Specific T Cells in Mice Content Test Stimulus Kit  No reviews	20T/100T
abs57019	Hepa 1-6 mouse tumor antigen specific T cell content detection stimulation kit	20T/100T
abs57022	AKR Esophageal Cancer Mouse Tumor Antigen-specific T Cell Content Detection Stimulation Kit	20T/100T
abs57023	Human tumor antigen-specific T cell content detection stimulation kit for non-small cell lung cancer	20T/100T