Anti-Tumor Necrosis Factor Receptor 2 Antibody Combined With Anti-PD-L1 Therapy Exerts Robust Antitumor Effects in Breast Cancer.

Qiang Fu,Wei Zhong,Jin Tong,Qian Shen,Liu Huang,Yi Cheng

doi:10.3389/fcell.2021.720472

Abstract

Breast cancer is a leading type of malignant tumor in women; however, the immunotherapy in breast cancer is still underappreciated. In this study, we demonstrated that tumor necrosis factor receptor 2 (TNFR2) is highly expressed in both breast tumor tissue and tumor-infiltrating immunosuppressive CD4+Foxp3+ regulatory T cells (Tregs). We found that TNFR2 antagonistic antibody reduced Foxp3 expression and the proliferation of Tregs and impaired the inhibitory effect of Tregs on CD4+CD25– effector T (Teff) cells in a dose-dependent manner. The treatment of anti-TNFR2 antibody not only inhibited the proliferation of breast tumor cells in vitro but also suppressed the tumorigenesis of murine mammary carcinoma 4T1 cells in vivo. Mice recovered from tumor growth also developed 4T1-specific immunity. Furthermore, we demonstrated that anti-TNFR2 antibody in combination with anti-PD-L1 exhibited augmented antitumor effects than monotherapy. Anti-TNFR2 treatment also tended to increase the expression of proinflammatory cytokines in tumor tissues. In conclusion, our study suggests that TNFR2 antagonist could potentially offer a clinical benefit as a single agent or in combination with immune checkpoint blockade treatment for breast cancer immunotherapy.

Highlights

Breast cancer is a major threat to the health of women in the world
Since the antitumor effect is mediated by immunostimulatory or immunosuppressive cytokines, we examined the expression of pro- and anti-inflammatory cytokines in tumor tissues after three doses of treatment. qRT-PCR analysis showed that antiTNFR2 therapy and combinatory therapy significantly increased the expression of IL17a, CXCL10, and IFNγ as compared with the isotype control (Figure 8A), while the expression of IL10, TNFα, TGF-β1, and tumor necrosis factor receptor 2 (TNFR2) was downregulated (Figure 8B)
Due to the insufficient infiltration of Teff cells and the accumulation of immunosuppressive Tregs in TME, immune evasion by tumor cells seriously hinders the efficacy of immunotherapy

Summary

Introduction

Breast cancer is a major threat to the health of women in the world. In 2020, it accounts for 30% of all new cancer cases in the United States, and more than 41,000 deaths occurred (Siegel et al, 2020). Tremendous research efforts have been made in early diagnosis, and the development of novel therapeutic strategies, the worldwide mortalities of breast cancer are still increasing every year. The most promising immunotherapy is the immune checkpoint blockage by anti-PD-1/PD-L antibodies, which achieves an objective response rate between 12 and 21% (Adams et al, 2019). TNFR2, Anti-PD-L1 and Breast Cancer than 10% of patients with metastasis (Emens, 2018). It is necessary to identify effective molecular targets and develop combination therapy for better treatment outcome

Methods

Results

Conclusion