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5-Aminolevulinic Acid-Mediated Photodynamic Therapy Can Target Aggressive Adult T Cell Leukemia/Lymphoma Resistant to Convention

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5-Aminolevulinic Acid-Mediated Photodynamic Therapy Can Target Aggressive Adult T Cell Leukemia/Lymphoma Resistant to Convention View metadata, citation and similar papers at core.ac.uk brought to you by CORE www.nature.com/scientificreportsprovided by Okayama University Scientific Achievement Repository OPEN 5‑aminolevulinic acid‑mediated photodynamic therapy can target aggressive adult T cell leukemia/lymphoma resistant to conventional chemotherapy Yasuhisa Sando1, Ken‑ichi Matsuoka1*, Yuichi Sumii1, Takumi Kondo1, Shuntaro Ikegawa1, Hiroyuki Sugiura1, Makoto Nakamura1, Miki Iwamoto1, Yusuke Meguri1, Noboru Asada1, Daisuke Ennishi1, Hisakazu Nishimori1, Keiko Fujii1, Nobuharu Fujii1, Atae Utsunomiya2, Takashi Oka1* & Yoshinobu Maeda1 Photodynamic therapy (PDT) is an emerging treatment for various solid cancers. We recently reported that tumor cell lines and patient specimens from adult T cell leukemia/lymphoma (ATL) are susceptible to specifc cell death by visible light exposure after a short‑term culture with 5‑aminolevulinic acid, indicating that extracorporeal photopheresis could eradicate hematological tumor cells circulating in peripheral blood. As a bridge from basic research to clinical trial of PDT for hematological malignancies, we here examined the efcacy of ALA‑PDT on various lymphoid malignancies with circulating tumor cells in peripheral blood. We also examined the efects of ALA‑PDT on tumor cells before and after conventional chemotherapy. With 16 primary blood samples from 13 patients, we demonstrated that PDT efciently killed tumor cells without infuencing normal lymphocytes in aggressive diseases such as acute ATL. Importantly, PDT could eradicate acute ATL cells remaining after standard chemotherapy or anti‑CCR4 antibody, suggesting that PDT could work together with other conventional therapies in a complementary manner. The responses of PDT on indolent tumor cells were various but were clearly depending on accumulation of protoporphyrin IX, which indicates the possibility of biomarker‑guided application of PDT. These fndings provide important information for developing novel therapeutic strategy for hematological malignancies. Photodynamic therapy (PDT) is a therapeutic modality that specifcally kills target cancer cells through the combination of a photosensitizer and light irradiation. PDT is used for skin diseases such as actinic keratosis because it can be administered repeatedly and does not cause scars1. In addition, PDT has also been studied for malignant diseases such as head and neck cancer, esophageal cancer, prostate cancer and bladder cancer 2–7. A natural amino acid, 5-aminolevulinic acid (5-ALA), is a precursor of protoporphyrin IX (PpIX) in the heme biosynthesis pathway. PpIX is a fuorescent photosensitizer that generates singlet oxygen (1O2) in cells exposed to visible light. PpIX selectively accumulates in tumor cells because of metabolic abnormalities. Since tumor cells are abnormal in the heme biosynthetic pathway, PpIX specifcally accumulates in tumor cells. By this property, 5-ALA is used for photodynamic diagnosis (PDD) and PDT 8,9. For malignant glioma and bladder cancer, intra- operative visualization with 5-ALA can remove tumors more completely than without 5-ALA10,11. ALA-PDT has also been approved to treat the precancerous disease actinic keratosis12. However, there are only a few studies on the application of ALA-PDT for hematological malignancies13,14. Adult T cell leukemia/lymphoma (ATL) is an aggressive T cell malignancy caused by human T cell leukemia virus type 1 (HTLV-1)15. ATL is classifed into 4 clinical subtypes: acute, lymphoma, chronic, and smoldering 16. Te acute and lymphoma types of ATL, which are considered aggressive ATL, have a dismal prognosis, mainly 1Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, Okayama 700-8558, Japan. 2Department of Hematology, Imamura General Hospital, Kagoshima, Japan. *email: [email protected]; oka@ md.okayama-u.ac.jp Scientifc Reports | (2020) 10:17237 | https://doi.org/10.1038/s41598-020-74174-x 1 Vol.:(0123456789) www.nature.com/scientificreports/ A Visible Light 5-ALA Irradiattion exposure Wash (66 min) incubation PBMC (4 hours) purification Before PDT After PDT Analysis Analysis B. Pt.9 ATL acute type C. Pt.7ATL acute type D. Pt.8 ATL acute type Live CD4+ T cells Live CD4+ T cells Live CD4+ T cells Before PDT After PDT Before PDTAfter PDT Before PDTAfter PDT 5-ALA 1mM 5-ALA 1mM 5-ALA 1mM 3 3 3 3 3 3 10 10 10 10 10 10 2 2 2 2 2 2 10 10 10 10 10 10 CD7 CD7 CD7 91.5 CD7 50.0 CD7 CD7 1 1 1 1 1 1 10 10 10 10 10 10 0 0 0 0 0 0 10 10 10 78.8610 .5 10 84.3 10 12.0 -1 -1 -1 -1 -1 -1 10 10 10 10 10 10 -1 0 1 2 3 -1 0 1 2 3 -1 0 1 2 3 -1 0 1 2 3 -2 -1 0 1 2 3 -2 -1 0 1 2 3 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 CADM1 CADM1 CADM1 CADM1 CADM1 CADM1 CD4+ CADM1+ ATL cells CD4+ CADM1+ ATL cells CD4+ CADM1+ ATL cells Shaded Irradiated Shaded Irradiated Shaded Irradiated 3 3 3 3 3 3 V 5-ALA 500 10 10 5-ALA V 10 10 5-ALA V 10 10 2.0K 3.1 1.0 1.4 0.5 120 6.4 1.52.8 0.6 0.5 0.1 0.7 0.1 400 2 2 2 2 2 2 0.1 10 10 0.1 10 10 0.1 10 10 1.5K 90 300 1 1 1 1 1 1 0mM 10 10 0mM 10 10 0mM 1.0K 10 10 60 200 Annexin Annexin Annexin 0 0 0 0 0 0 10 10 30 10 10 500 10 10 100 -1 -1 0 -1 -1 0 -1 -1 0 10 94.5 10 97.4 10 94.4 10 95.8 10 99.4 10 99.1 -1 0 1 2 3 -1 0 1 2 3 -1 0 1 2 3 -1 0 1 2 3 -1 0 1 2 3 10 10 10 10 10 -1 0 1 2 3 -1 0 1 2 3 10 10 10 10 10 -1 0 1 2 3 -1 0 1 2 3 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 3 3 3 3 3 3 10 10 10 10 10 10 1.5K 600 3.3 1.0 3.6 16.4 150 7.0 1.4 11.7 48.8 0.3 0.1 0.6 11.7 2 2 2 2 2 2 13.4 10 10 24.8 10 10 5.3 10 10 1.0K 400 100 1 1 1 1 1 1 0.25mM 10 10 0.25mM 10 10 0.25mM 10 10 500 200 50 0 0 0 0 0 0 10 10 10 10 10 10 0 -1 -1 0 -1 -1 0 -1 -1 10 94.8 10 78.9 10 91.1 10 33.9 10 99.6 10 86.6 -1 0 1 2 3 -1 0 1 2 3 -1 0 1 2 3 10 10 10 10 10 -1 0 1 2 3 -1 0 1 2 3 10 10 10 10 10 -1 0 1 2 3 -1 0 1 2 3 10 10 10 10 10 -1 0 1 2 3 -1 0 1 2 3 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 3 3 3 3 3 3 1.0K 10 10 10 10 10 10 2.8 0.8 2.1 83.7 6.5 1.8 1.0 72.0 4.0K 0.4 0.1 0.1 86.3 2 2 300 2 2 2 2 800 91.2 10 10 92.9 10 10 98.8 10 10 3.0K 600 1 1 200 1 1 1 1 10 10 10 10 10 10 1mM 1mM 1mM 2.0K 400 0 0 100 0 0 0 0 10 10 10 10 1.0K 10 10 200 0 -1 -1 0 -1 -1 0 -1 -1 10 93.2 10 11.3 10 91.4 10 1.1 10 99.4 10 0.4 -1 0 1 2 3 -1 0 1 2 3 -1 0 1 2 3 10 10 10 10 10 -1 0 1 2 3 -1 0 1 2 3 10 10 10 10 10 -1 0 1 2 3 -1 0 1 2 3 10 10 10 10 10 -1 0 1 2 3 -1 0 1 2 3 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 PpIX FVD PpIX FVD PpIX FVD Figure 1. PDT induces necrosis of ATL cells from patient blood. (A) Te experimental procedure of PDT is shown. PBMCs were purifed from peripheral blood samples and then were incubated in the presence of various concentrations of 5-ALA for 4 h. Afer the removal of 5-ALA, PBMCs were irradiated with 630 nm visible light for 1 h. Samples were promptly analyzed by fow cytometry. (B) Analyses of three patients with ATL are shown. Live CD4+ T cells show the population of CD4+CD7-CADM1- cells. ATL cells were identifed by CD4, CD7 and CADM1 as shown in the upper panels of Fig.
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