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Tumor Transplantation for Assessing the Dynamics of Tumor-Infiltrating CD8+ T Cells in Mice
Published on: June 12, 2021
Tissue factor overexpression in triple-negative breast cancer promotes immune evasion by impeding T-cell infiltration
Zhiqiang Ren1, Yinyin Xue1, Liang Liu1
1Department of Pharmacology, Fudan University School of Pharmacy, Shanghai, 201203, China.
Abstract:
Triple-negative breast cancer (TNBC) remains a most deadly human malignancy with limited response to chemotherapy, targeted therapy and immunotherapy. Tumor immunoenvironment plays an increasingly important role in therapy outcome. Tissue factor (TF) is the target of the FDA-approved ADC Tivdak. HuSC1-39 is the parent antibody of MRG004A, a clinical stage TF-ADC (NCT04843709). Here, we employed HuSC1-39 (termed "anti-TF") to investigate the role of TF in regulating immune-tolerance in TNBC. We found that patients with aberrant TF expression had a poor prognosis and low immune effector cell infiltration, characterizing as "cold tumor". In the 4T1 TNBC syngeneic mouse model, knockout of tumor cell TF inhibited tumor growth and increased tumor infiltration of effector T cell, which was not dependent on the clotting inhibition. In an immune-reconstituted M-NSG mouse model of TNBC, anti-TF inhibited tumor growth, which was further enhanced by a dual-targeting anti-TF&TGFβR fusion protein. There were diminished P-AKT and P-ERK signaling and profound tumor cell death in treated tumors. Transcriptome analyses and immunohistochemistry revealed a dramatically improved tumor immunoenvironment including the increase of effector T cells, decrease of Treg cells and the transformation of tumor into "hot tumor". Moreover, employing qPCR analysis and T cell culture, we further demonstrated that TF expression in tumor cells is sufficient to block the synthesis and secretion of T cell-recruiting chemokine CXCL9/10/11. Treatment of TF-high TNBC cells with anti-TF or TF-knockout all stimulated CXCL9/10/11 production, promoted T cell migration and effector function. Thus, we have identified a new mechanism of TF in TNBC tumor progression and therapy resistance.
Insights
Tissue factor (TF) drives immune suppression in triple-negative breast cancer (TNBC). Targeting TF with antibodies can reverse this, enhancing anti-tumor immunity and improving outcomes for this deadly malignancy.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Triple-negative breast cancer (TNBC) presents a significant clinical challenge due to limited treatment options and poor response to current therapies.
- The tumor immunoenvironment critically influences therapeutic success, with immune-tolerant
- cold tumors
- often resistant to treatment.
Purpose of the Study:
- To investigate the role of Tissue Factor (TF) in regulating immune tolerance within the TNBC tumor microenvironment.
- To explore the therapeutic potential of targeting TF to overcome immune evasion and enhance anti-tumor immunity in TNBC.
Main Methods:
- Utilized a HuSC1-39 antibody (anti-TF) in TNBC models, including TF-knockout and immune-reconstituted mouse models.
- Assessed tumor growth, immune cell infiltration (effector T cells, Treg cells), signaling pathways (P-AKT, P-ERK), and chemokine expression (CXCL9/10/11).
- Performed transcriptome analysis and immunohistochemistry to characterize changes in the tumor immunoenvironment.
Main Results:
- Aberrant TF expression in TNBC patients correlated with poor prognosis and reduced immune cell infiltration.
- TF knockout or anti-TF treatment inhibited tumor growth and increased effector T cell infiltration in mouse models.
- Targeting TF reversed immune suppression, transforming tumors into
- hot tumors
- with enhanced T cell function and reduced immunosuppressive signaling.
- TF was found to directly inhibit the production of T cell-recruiting chemokines CXCL9/10/11.
Conclusions:
- Tissue Factor plays a crucial role in establishing immune tolerance and promoting progression in triple-negative breast cancer.
- Targeting TF represents a promising strategy to enhance anti-tumor immunity and overcome therapeutic resistance in TNBC.
- TF inhibition can restore chemokine production, promote T cell recruitment, and improve effector function, offering a novel therapeutic avenue.
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