Photosensitizer IR700DX-6T- and IR700DX-mbc94-mediated photodynamic therapy markedly elicits anticancer immune responses during treatment of pancreatic cancer

Dawei Zhang; Qing Xie; Yang Liu; Zongyan Li; Haiyan Li; Shiying Li; Zhen Li; Jing Cui; Meng Su; Xiaofeng Jiang; Ping Xue; Mingfeng Bai

doi:10.1016/j.phrs.2021.105811

Photosensitizer IR700DX-6T- and IR700DX-mbc94-mediated photodynamic therapy markedly elicits anticancer immune responses during treatment of pancreatic cancer

Pharmacol Res. 2021 Oct:172:105811. doi: 10.1016/j.phrs.2021.105811. Epub 2021 Aug 12.

Authors

Dawei Zhang¹, Qing Xie², Yang Liu², Zongyan Li³, Haiyan Li⁴, Shiying Li⁵, Zhen Li⁶, Jing Cui⁷, Meng Su², Xiaofeng Jiang³, Ping Xue⁸, Mingfeng Bai⁹

Affiliations

¹ Department of Hepatobiliary Surgery, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510260, China; Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
² Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
³ Department of Hepatobiliary Surgery, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510260, China.
⁴ Department of Breast Surgery, the Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510650, China.
⁵ Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, Guangdong 511436, China.
⁶ Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Fourth General Surgery Department, the Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning 110000, China.
⁷ Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Nuclear Medicine, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, China.
⁸ Department of Hepatobiliary Surgery, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510260, China. Electronic address: drxueping@21cn.com.
⁹ Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA. Electronic address: mingfeng.bai@vanderbilt.edu.

PMID: 34390852
DOI: 10.1016/j.phrs.2021.105811

Abstract

Background/aims: IR700DX-6T and IR700DX-mbc94 are two chemically synthesized photosensitizers (PSs) that target the translocator protein (TSPO) and type 2 cannabinoid receptor (CB₂R), respectively, for photodynamic therapy (PDT) of cancer. Recently, we found that IR700DX-6T and IR700DX-mbc94 exhibited high selectivity and efficiency in PDT for breast cancer and malignant astrocytoma. Yet, the phototherapeutic effects of the PSs on pancreatic cancer and underlying mechanisms remain unknown. This study investigated the effect of IR700DX-6T- or IR700DX-mbc94-PDT on pancreatic cancer and whether the treatment involves eliciting anticancer immune responses in support of superior therapeutic efficacy.

Methods: Four pancreatic cancer cell lines were used for in vitro studies. C57BL/6 mice bearing pancreatic cancer cell-derived xenografts were generated for in vivo studies regarding the therapeutic effects of IR700DX-6T-PDT and IR700DX-mbc94-PDT on pancreatic cancer. The immunostimulatory or immunosuppressive effects of IR700DX-6T-PDT and IR700DX-mbc94-PDT were examined by detecting CD8⁺ T cells, regulatory T cells (T_regs), and dendritic cells (DCs) using flow cytometry and immunohistochemistry (IHC).

Results: TSPO and CB₂R were markedly upregulated in pancreatic cancer cells and tissues. Both IR700DX-6T-PDT and IR700DX-mbc94-PDT significantly inhibited pancreatic cancer cell growth in a dose- and time-dependent manner. Notably, assessment of anticancer immune responses revealed that both IR700DX-6T-PDT and IR700DX-mbc94-PDT significantly induced CD8⁺ T cells, promoted maturation of DCs, and suppressed T_regs, with stronger effects exerted by IR700DX-6T-PDT compared to IR700DX-mbc94-PDT.

Conclusions: IR700DX-6T-PDT and IR700DX-mbc94-PDT involves eliciting anticancer immune responses. Our study has also implicated that PDT in combination with immunotherapy holds promise to improve therapeutic efficacy for patients with pancreatic cancer.

Keywords: CD8+T cell; Dendritic cell; Pancreatic cancer; Photodynamic therapy; Photosensitizer; Regulatory T cell.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine Triphosphate / metabolism
Animals
CD8-Positive T-Lymphocytes / drug effects
CD8-Positive T-Lymphocytes / immunology
Cell Line, Tumor
Cell Survival / drug effects
Dendritic Cells / drug effects
Dendritic Cells / immunology
Humans
Indoles / pharmacology
Indoles / therapeutic use*
Lymph Nodes / cytology
Lymph Nodes / immunology
Mice
Mice, Inbred C57BL
Organosilicon Compounds / pharmacology
Organosilicon Compounds / therapeutic use*
Pancreas / metabolism
Pancreatic Neoplasms / drug therapy*
Pancreatic Neoplasms / immunology
Pancreatic Neoplasms / metabolism
Photochemotherapy*
Photosensitizing Agents / pharmacology
Photosensitizing Agents / therapeutic use*
Receptor, Cannabinoid, CB2 / metabolism
Receptors, GABA / metabolism
Spleen / cytology
Spleen / immunology
T-Lymphocytes, Regulatory / drug effects
T-Lymphocytes, Regulatory / immunology

Substances

Bzrp protein, mouse
IR700DX-mbc94
Indoles
Organosilicon Compounds
Photosensitizing Agents
Receptor, Cannabinoid, CB2
Receptors, GABA
Adenosine Triphosphate