Regorafenib enhances antitumor immune efficacy of anti-PD-L1 immunotherapy on oral squamous cell carcinoma

I-Tsang Chiang; Yuan-Hao Lee; Zhao-Lin Tan; Fei-Ting Hsu; Hsi-Feng Tu

doi:10.1016/j.biopha.2022.112661

Regorafenib enhances antitumor immune efficacy of anti-PD-L1 immunotherapy on oral squamous cell carcinoma

Biomed Pharmacother. 2022 Mar:147:112661. doi: 10.1016/j.biopha.2022.112661. Epub 2022 Jan 26.

Authors

I-Tsang Chiang¹, Yuan-Hao Lee², Zhao-Lin Tan³, Fei-Ting Hsu⁴, Hsi-Feng Tu⁵

Affiliations

¹ Department of Radiation Oncology, Show Chwan Memorial Hospital, Changhua 500, Taiwan, ROC; Department of Radiation Oncology, Chang Bing Show Chwan Memorial Hospital, Lukang, Changhua 505, Taiwan, ROC; Department of Medical Imaging and Radiological Sciences, Central Taiwan University of Science and Technology, Taichung 406, Taiwan, ROC; Medical administrative center, Show Chwan Memorial Hospital, Changhua 500, Taiwan, ROC.
² Department of Biomedical Imaging and Radiological Science, China Medical University, Taichung 404, Taiwan, ROC; Department of Radiation Physics, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
³ Department of Biological Science and Technology, China Medical University, Taichung 404, Taiwan, ROC.
⁴ Department of Biological Science and Technology, China Medical University, Taichung 404, Taiwan, ROC. Electronic address: sakiro920@mail.cmu.edu.tw.
⁵ Department of Dentistry, Dental School, National Yang Ming Chiao Tung University, Taipei 112, Taiwan, ROC; Department of Dentistry, National Yang Ming Chiao Tung University Hospital, Yilan 260, Taiwan, ROC. Electronic address: hftu@nycu.edu.tw.

PMID: 35092865
DOI: 10.1016/j.biopha.2022.112661

Abstract

Oral squamous cells carcinoma (OSCC) is the most common oral malignancy that majorly originated from oral cavity. Though the prognostic and predictive value of targeting checkpoint molecules has been reported on OSCC, the treatment efficacy of monotherapy is remaining limited. Several studies suggested that multikinase inhibitors may show potential to facilitate anti-PD-L1-induced anti-tumor immunity. Regorafenib, an oral multikinase inhibitor has been approved by FDA for various types of cancer treatment. Here, we aim to identify whether regorafenib may boost anti-tumor immunity of anti-PD-L1 in MOC1-bearing OSCC animal model. The alteration of immune cells such as M1/M2-like macrophages (MΦ), cytotoxicity T cells, regulatory T cells (Tregs), and myeloid-derived suppressor cells (MDSCs) after combination of anti-PD-L1 and regorafenib was validated by flow cytometry and immunohistochemistry staining. The combination index analysis (CI=0.89) supported that regorafenib effectively induce anti-OSCC efficacy of anti-PD-L1. Combination of anti-PD-L1 and regorafenib may not only trigger the polarization of M1-like MΦ (CD11b⁺CD86⁺) in mice bone marrow (BM) and spleen (SP), but also induce the accumulation and function of CD8⁺ T cells in tumor-draining lymph node (TDLN) and tumor. In addition, immunosuppressive related cells (MDSCs and Treg) and factors were all decreased by combination therapy in BM, SP and tumor. In sum, regorafenib may improve anti-OSCC efficacy of anti-PD-L1 through systemically and locally upregulating the immunostimulation immunity and suppressing immunosuppression immunity.

Keywords: Anti-PD-L1; Antitumor-induced immunity; Oral squamous cells carcinoma; Regorafenib.

MeSH terms

Animals
Antineoplastic Combined Chemotherapy Protocols
Carcinoma, Squamous Cell / pathology*
Cell Line, Tumor
Cell Survival / drug effects
Immune Checkpoint Inhibitors / administration & dosage
Immune Checkpoint Inhibitors / pharmacology*
Macrophages / drug effects
Male
Mice
Mice, Inbred C57BL
Mouth Neoplasms / pathology*
Phenotype
Phenylurea Compounds / administration & dosage
Phenylurea Compounds / pharmacology*
Pyridines / administration & dosage
Pyridines / pharmacology*

Substances

Immune Checkpoint Inhibitors
Phenylurea Compounds
Pyridines
regorafenib