Transforming growth factor-β blockade modulates tumor mechanical microenvironment for enhanced antitumor efficacy of photodynamic therapy

Nanoscale ◽  
2021 ◽  
Author(s):  
Jitang Chen ◽  
Si Li ◽  
Xin Liu ◽  
Sha Liu ◽  
Chen Xiao ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Photodynamic Therapy ◽  
Growth Factor ◽  
Cancer Treatment ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Clinical Settings ◽  
Mechanical Microenvironment

Photodynamic therapy (PDT) is frequently used for cancer treatment in the clinical settings. However, its applications in stroma-rich solid tumors, e.g., triple negative breast cancer, are limited by the abnormal...

scholarly journals The testis protein ZNF165 is a SMAD3 cofactor that coordinates oncogenic TGFβ signaling in triple-negative breast cancer

2020 ◽  
Author(s):  
Zane A. Gibbs ◽  
Luis C. Reza ◽  
Chun-Chun Cheng ◽  
Jill M. Westcott ◽  
Kathleen McGlynn ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Transforming Growth Factor ◽  
Zinc Finger Protein ◽  
Transforming Growth Factor Β ◽  
Aberrant Expression ◽  
Growth And Survival ◽  
Ct Antigens

ABSTRACTCancer/testis (CT) antigens are proteins whose expression is normally restricted to germ cells yet aberrantly activated in tumors, where their functions remain relatively cryptic. Here we report that ZNF165, a CT antigen frequently expressed in triple-negative breast cancer (TNBC), associates with SMAD3 to modulate transcription of transforming growth factor β (TGFβ)-dependent genes and thereby promote growth and survival. In addition, we identify the KRAB zinc finger protein, ZNF446, and its associated tripartite motif protein, TRIM27, as obligate components of the ZNF165-SMAD3 complex that also support tumor cell viability. Importantly, we find that TRIM27 alone is necessary for ZNF165 transcriptional activity and is required for orthotopic tumor growth in vivo. Our findings indicate that aberrant expression of a testis-specific transcription factor is sufficient to co-opt somatic transcriptional machinery to drive a pro-tumorigenic gene expression program.

scholarly journals Targeting transforming growth factor-β2 by antisense oligodeoxynucleotide accelerates T cell-mediated tumor rejection in a humanized mouse model of triple-negative breast cancer

2021 ◽  
Author(s):  
Hong Kyu Lee ◽  
Hyeong-Jin Ji ◽  
Sang-Kyung Shin ◽  
Jihye Koo ◽  
Tae Hun Kim ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
T Cell ◽  
Growth Factor ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Transforming Growth Factor ◽  
Cytotoxic T Cells ◽  
Tumor Rejection ◽  
Antisense Oligodeoxynucleotide

Abstract Background: Transforming growth factor (TGF-β) pathway mediates suppression of anti-tumor immunity, and is associated with poor prognosis in triple-negative breast cancer (TNBC). Methods: In this study, we generated a humanized animal model by transplanting human peripheral blood mononuclear cells into immunodeficient mice followed by inoculation of MDA-MB-231 cells, and subsequently analyzed the role of TGF-β2 in the interaction between human T cells and human tumor cells. Results: Following reconstitution of the human immune system, inhibition of TGF-β signaling by TGF-β2 antisense oligodeoxynucleotide (TASO) resulted in accelerated tumor growth inhibition. TGF-β2 inhibition also resulted in downregulation of peripheral Foxp3+ regulatory T cells (Treg), whereas no effect was seen in the expression of CD8+ cytotoxic T cells. Analysis of the TASO-treated mice serum revealed elevated levels of human IFN-γ and reduced levels of human IL-10 and TGF-β2. Moreover, TGF-β2 inhibition resulted in increased CD8+ T cell infiltration, whereas the reduced infiltration of Tregs into the tumor partly resulted from decreased expression of CCL22. Decreased intra-tumoral Tregs facilitated the activation of cytotoxic T cells, associated with increased granzyme B expression. Conclusion: These results indicate that TASO potentiated T-cell mediated antitumor immunity, and it is proposed that TGF-β2 may be a promising target in the immunotherapeutic strategy of TNBC.

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