Cancer cell-binding peptide fused Fc domain activates immune effector cells and blocks tumor growth.

Anne Mobergslien,Vlada Vasovic,Mouldy Sioud,Qian Peng

doi:10.18632/oncotarget.12445

Abstract

Therapeutic strategies aiming at mobilizing immune effector cells to kill tumor cells independent of tumor mutational load and MHC expression status are expected to benefit cancer patients. Recently, we engineered various peptide-Fc fusion proteins for directing Fcg receptor-bearing immune cells toward tumor cells. Here, we investigated the immunostimulatory and anti-tumor effects of one of the engineered Fc fusion proteins (WN-Fc). In contrast to the Fc control, soluble WN-Fc-1 fusion protein activated innate immune cells (e.g. monocytes, macrophages, dendritic cells, NK cells), resulting in cytokine production and surface display of the lytic granule marker CD107a on NK cells. An engineered Fc-fusion variant carrying two peptide sequences (WN-Fc-2) also activated immune cells and bound to various cancer cell types with high affinity, including the murine 4T1 breast carcinoma cells. When injected into 4T1 tumor-bearing BALB/c mice, both peptide-Fc fusions accumulated in tumor tissues as compared to other organs such as the lungs. Moreover, treatment of 4T1 tumor-bearing BALB/c mice by means of two intravenous injections of the WN-Fc fusion proteins inhibited tumor growth with WN-Fc-2 being more effective than WN-Fc-1. Treatment resulted in tumor infiltration by T cells and NK cells. These new engineered WN-Fc fusion proteins may be a promising alternative to existing immunotherapies for cancer.

Highlights

In spite of significant progress in recent years towards the development of new targeted therapies, cancer is still a largely unmet medical need [1]
The engagement of the antibody Fc domain with the Fcγ receptors expressed by innate immune cells such as natural killer (NK) cells and macrophages triggers antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis of tumor cells [9, 10]
Given the central role played by NK cells in cancer immunotherapy [9], we evaluated the relative ability of soluble WN-Fc-1 and WN-Fc-2 to stimulate NK cell FcγRIIIa receptor

Summary

Introduction

In spite of significant progress in recent years towards the development of new targeted therapies, cancer is still a largely unmet medical need [1]. In contrast to checkpoint inhibitors, the clinical efficacy of several monoclonal antibodies (mAbs) such as retixumab, herceptin, and cetixumab, is largely dependent on the patient’s innate immune effector cells [7]. The engagement of the antibody Fc domain with the Fcγ receptors expressed by innate immune cells such as natural killer (NK) cells and macrophages triggers antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis of tumor cells [9, 10]. FcγR activation can be stimulatory or inhibitory to effector cells, depending on which receptor is triggered and which cells are activated [12]. With respect to cancer immunotherapy, NK cells are central in that they express only the activating FcγRIIIa receptor (CD16) and no inhibitory antibody receptors underscoring a major role in promoting tumor cell killing [13]

Methods

Results

Conclusion