Targeting M-MDSCs enhances the therapeutic effect of BNCT in the 4-NQO-induced murine head and neck squamous cell carcinoma model

Chun-Hsiang Chang; Chi-Jui Chen; Ching-Fang Yu; Hui-Yu Tsai; Fang-Hsin Chen; Chi-Shiun Chiang

doi:10.3389/fonc.2023.1263873

Targeting M-MDSCs enhances the therapeutic effect of BNCT in the 4-NQO-induced murine head and neck squamous cell carcinoma model

Front Oncol. 2023 Oct 2:13:1263873. doi: 10.3389/fonc.2023.1263873. eCollection 2023.

Authors

Chun-Hsiang Chang¹, Chi-Jui Chen¹, Ching-Fang Yu^{2

3}, Hui-Yu Tsai⁴, Fang-Hsin Chen⁴, Chi-Shiun Chiang^{1

4}

Affiliations

¹ Department of Biomedical Engineering and Environment Sciences, National Tsing Hua University, Hsinchu, Taiwan.
² Institute for Radiological Research, Chang Gung University, Taoyuan, Taiwan.
³ Department of Radiation Oncology, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Taiwan.
⁴ Institute of Nuclear Engineering and Science, National Tsing Hua University, Hsinchu, Taiwan.

Abstract

Purpose: Malignant head and neck squamous cell carcinoma (HNSCC) is characterized by a poor prognosis and resistance to conventional radiotherapy. Infiltrating myeloid-derived suppressive cells (MDSCs) is prominent in HNSCC and is linked to immune suppression and tumor aggressiveness. This study aimed to investigate the impact of boron neutron capture therapy (BNCT) on the MDSCs in the tumor microenvironment and peripheral blood and to explore the potential for MDSCs depletion combined with BNCT to reactivate antitumor immunity.

Methods and materials: Carcinogen, 4-NQO, -induced oral tumors were irradiated with a total physical dose of 2 Gy BNCT in Tsing Hua Open Reactor (THOR). Flow cytometry and immunohistochemistry accessed the dynamics of peripheral MDSCs and infiltrated MDSCs within the tumor microenvironment. Mice were injected with an inhibitor of CSF-1 receptor (CSF-1R), PLX3397, to determine whether modulating M-MDSCs could affect mice survival after BNCT.

Results: Peripheral CD11b⁺Ly6C^highLy6G^- monocytic-MDSCs (M-MDSCs), but not CD11b⁺Ly6C^loLy6G^high polymorphonuclear-MDSCs (PMN-MDSCs), increased as tumor progression. After BNCT treatment, there were temporarily decreased and persistent increases of M-MDSCs thereafter, either in peripheral blood or in tumors. The administration of PLX-3397 hindered BNCT-caused M-MDSCs infiltration, prolonged mice survival, and activated tumor immunity by decreasing tumor-associated macrophages (TAMs) and increasing CD8⁺ T cells.

Conclusion: M-MDSCs were recruited into 4-NQO-induced tumors after BNCT, and their number was also increased in peripheral blood. Assessment of M-MDSCs levels in peripheral blood could be an index to determine the optimal intervention window. Their temporal alteration suggests an association with tumor recurrence after BNCT, making M-MDSCs a potential intervention target. Our preliminary results showed that PLX-3397 had strong M-MDSCs, TAMs, and TIL (tumor-infiltrating lymphocyte) modulating effects that could synergize tumor control when combined with BNCT.

Keywords: 4-NQO; BNCT; CSF-1R inhibitor; HNSCC; MDSCs.

Grants and funding

This work was supported by grant number NTHU- 110A0184K6, NTHU-112Q2704E1, and NTHU-112QI047E1 to C-SC and NSTC-111-2628-B-007-010, NSTC-109-2314-B-007- 008-MY3, and NTHU-112F7MCXE1 to FC, and NSTC-112-2314- B-182-054-MY3, and UMRPD1N0061 to C-FY.