Abstract

The induction of apoptosis is a direct way to eliminate tumor cells and improve cancer therapy. Apoptosis is tightly controlled by the balance of pro- and antiapoptotic Bcl-2 proteins. BH3 mimetics neutralize the antiapoptotic function of Bcl-2 proteins and are highly promising compounds inducing apoptosis in several cancer entities including pediatric malignancies. However, the clinical application of BH3 mimetics in solid tumors is impeded by the frequent resistance to single BH3 mimetics and the anticipated toxicity of high concentrations or combination treatments. One potential avenue to increase the potency of BH3 mimetics is the development of immune cell-based therapies to counteract the intrinsic apoptosis resistance of tumor cells and sensitize them to immune attack. Here, we describe spheroid cultures of pediatric cancer cells that can serve as models for drug testing. In these 3D models, we were able to demonstrate that activated allogeneic Natural Killer (NK) cells migrated into tumor spheroids and displayed cytotoxicity against a wide range of pediatric cancer spheroids, highlighting their potential as anti-tumor effector cells. Next, we investigated whether treatment of tumor spheroids with subtoxic concentrations of BH3 mimetics can increase the cytotoxicity of NK cells. Notably, the cytotoxic effects of NK cells were enhanced by the addition of BH3 mimetics. Treatment with either the Bcl-XL inhibitor A1331852 or the Mcl-1 inhibitor S63845 increased the cytotoxicity of NK cells and reduced spheroid size, while the Bcl-2 inhibitor ABT-199 had no effect on NK cell-mediated killing. Taken together, this is the first study to describe the combination of BH3 mimetics targeting Bcl-XL or Mcl-1 with NK cell-based immunotherapy, highlighting the potential of BH3 mimetics in immunotherapy.

Highlights

  • Considerable progress has been made in the treatment of childhood cancer, refractory disease is still associated with a poor prognosis

  • BH3 mimetics efficiently kill tumor spheroids To explore whether the cell line-based spheroids can serve as platforms for drug testing we investigated the response to apoptosis-inducing BH3 mimetics

  • The combination of BH3 mimetics and Natural Killer (NK) cells increases tumor cell killing Based on these findings, we evaluated whether activated NK cells can be used in combination with BH3 mimetics to increase spheroid killing at subtoxic concentrations of BH3 mimetics

Read more

Summary

Introduction

Considerable progress has been made in the treatment of childhood cancer, refractory disease is still associated with a poor prognosis. One approach in the treatment of cancer is the direct induction of apoptosis in tumor cells. While Bcl-2 is mainly expressed in lymphoid malignancies, the related proteins Bcl-XL and Mcl-1 are frequently amplified and overexpressed in solid tumors including pediatric cancers [4, 5]. Several compounds have been developed that bind and neutralize the antiapoptotic Bcl-2 proteins. Thereby, these inhibitors antagonize the antiapoptotic Bcl-2 proteins in a similar manner as BH3-only proteins, and are called BH3 mimetics. With ABT-199 (venetoclax), the first BH3 mimetic selectively inhibiting Bcl-2 has been approved and is transforming the treatment of lymphoid malignancies like chronic lymphocytic leukemia [6, 7]. The potential of BH3 mimetics targeting Bcl-XL or Mcl-1 has been underscored by multiple studies showing their apoptosis-inducing capacities in Received: 29 September 2021 Revised: 3 December 2021 Accepted: 16 December 2021

Objectives
Methods
Results
Conclusion
Full Text
Published version (Free)

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call