Skip to main content
ASTRO 2024 Main banner
Icon Legend
Presentation Icons
Event Add-on
Event Add-on
In Person Only
In Person Only
Off-site Event
Off-site Event
Location: Marriott Marquis
Location: Marriott Marquis
Back
Main Session

QP 24 - Bio 6: Immunotherapy and Immune Response II

1138 - Bcl-2 Inhibitor Combined with Radiotherapy and Anti-Tumor Immune Response through Inducing Immunogenic Cell Death

Wednesday, October 2, 2024
10:40 AM – 10:45 AM ET
Location: Room 143
M. Ma1, J. Yuan2, Z. Zhang3, D. Chen4, and J. Yu5; 1Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China, 2Department of Radiation Oncology and Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China, 3Shandong Cancer Hospital and Institute, Jinan, Shandong, China, 4Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China, 5Shandong Cancer Hospital and Institute, Jinan, China

Purpose/Objective(s):

Escape from apoptosis is one of the main demeanor characters of cancer cells. The imbalance in the expression of anti-apoptotic proteins (Bcl-2, Bcl-xL, etc) and pro-apoptotic proteins (Bax, Bak, etc) within the Bcl-2 protein family is a key factor leading to radiotherapy resistance in tumor cells. Previous studies have confirmed that targeting Bcl-2 can overcome tumor radiotherapy resistance by promoting cell apoptosis in various types of cancer. However, whether Bcl-2 inhibitor combined with radiotherapy can induce other forms of cell death in tumor cells and affect the tumor immune microenvironment remains unknown. This study aims to explore the regulatory effects of Bcl-2 inhibitor (BGB-11417) combined with radiotherapy on immunogenic cell death and its impact on the tumor immune microenvironment. Materials/

Methods:

BGB-11417 combined with radiotherapy was used to treat tumor cells CMT167, MC38 and CT26. Immunogenic cell death and related signaling pathways were detected using flow cytometry, immunofluorescence confocal microscopy, Western Blot, etc. BGB-11417 alone was used to treat macrophages RAW264.7 and BMDM. The polarization and related pathways were assessed using qPCR, flow cytometry, and Western Blot. Subcutaneous transplant tumor models were established in C57BL/6 mices, treated with BGB-11417 combined with radiotherapy, and growth curves were recorded. Flow cytometry was used to detect macrophage polarization in the tumor immune microenvironment.
Results:

BGB-11417 combined with radiotherapy promoted immunogenic cell death in tumor cells, which include the release of ATP, IL-1ß, and the extracellular expression of calreticulin, MHC-I molecules. It also enhanced the release of type I interferon via activating the cGAS-STING pathway in tumor cells. All of these contributed to the infiltration of Gzmb+CD8+T cells in the tumor immune microenvironment. Futhermore, BGB-11417 alone activated the NF-?B pathway in macrophages, including the phosphorylation and nuclear translocation of P65 protein, then enhanced the expression of M1 macrophage-related genes CD86, NOS2 and inhibited the expression of M2 macrophage-related genes CD206, Arg1, which can explain the polarization of macrophages toward M1 type in vivo. In brief, Bcl-2 combined with radiotherapy suppressed tumor growth by promoting the infiltration of Gzmb+CD8+T cells and polarization of macrophages toward M1 type.
Conclusion:

Our study demonstrates that the combination of Bcl-2 inhibitor and radiotherapy enhances the anti-tumor immune response via promoting immunogenic cell death in tumor cells, along with the infiltration of Gzmb+T cells and polarization of M2 to M1 macrophages in the tumor microenvironment. Collectively, our findings indicate that further clinical evaluation of BGB-11417 and radiotherapy as a combination strategy is warranted.