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.