Neoadjuvant chemoradiotherapy up-regulates PD-L1 in radioresistant colorectal cancer
Background: Combining radiotherapy (RT) with immune checkpoint inhibitors (ICIs) is a promising strategy that can enhance the therapeutic efficacy of ICIs. However, little is known about RT-induced changes in the expression of immune checkpoints, such as PD-L1, and their clinical implications in col...
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Elsevier
2025-03-01
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| Series: | Clinical and Translational Radiation Oncology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2405630824001836 |
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| author | Sung Uk Bae Hye Won Lee Jee Young Park Incheol Seo Jae-Min Cho Jin Young Kim Ju Yup Lee Yoo Jin Lee Seong Kyu Baek Nam Kyu Kim Sang Jun Byun Shin Kim |
| author_facet | Sung Uk Bae Hye Won Lee Jee Young Park Incheol Seo Jae-Min Cho Jin Young Kim Ju Yup Lee Yoo Jin Lee Seong Kyu Baek Nam Kyu Kim Sang Jun Byun Shin Kim |
| author_sort | Sung Uk Bae |
| collection | DOAJ |
| description | Background: Combining radiotherapy (RT) with immune checkpoint inhibitors (ICIs) is a promising strategy that can enhance the therapeutic efficacy of ICIs. However, little is known about RT-induced changes in the expression of immune checkpoints, such as PD-L1, and their clinical implications in colorectal cancer (CRC). This study aimed to investigate the association between responsiveness to RT and changes in PD-L1 expression in human CRC tissue and cell lines. Methods: Tissue specimens from preoperative biopsy via sigmoidoscopy and surgical resection were obtained from 24 patients with locally advanced rectal cancer (LARC) who underwent neoadjuvant chemoradiation therapy (CRT) between August 2016 and December 2017. Immunohistochemistry for PD-L1 in formalin-fixed paraffin-embedded tissue was performed from the endoscopic biopsy and surgical specimens. RNA sequencing was performed using 11 pairs of human LARC tissues before and after irradiation. After exposing human CRC cells to radiation, we investigated changes in the expression levels of PD-L1 and its regulatory signaling pathways. Results: Patients were classified by tumor regression grade into responders (grade 2; 9 patients, 37.5 %) and non-responders (grades 3, 4, or 5; 15 patients, 62.5 %). In the non-responder group, 13 patients had low PD-L1 expression, but neoadjuvant CRT increased PD-L1 expression in 7 patients (53.9 %) (McNemar’s test, p=0.034). CRT up-regulated PD-L1 in non-responder LARC tissues. Similarly, radiation increased PD-L1 in radioresistant DLD-1 cells more than in radiosensitive HCT116 cells, also affecting PD-L1-regulating genes and immune checkpoints in CRC cells. Conventional fractionated radiation treatment further increased PD-L1 in DLD-1 cells compared to HCT116 cells. Conclusions: This study demonstrated that radiation induces an increase in PD-L1 expression, which is more pronounced in radioresistant CRC, proving the theoretical framework for a combined treatment strategy with a PD-L1 blockade for locally advanced rectal cancer. |
| format | Article |
| id | doaj-art-27c09f99fe864c0fb4b6cf0509130e0c |
| institution | Kabale University |
| issn | 2405-6308 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Clinical and Translational Radiation Oncology |
| spelling | doaj-art-27c09f99fe864c0fb4b6cf0509130e0c2025-01-30T05:14:28ZengElsevierClinical and Translational Radiation Oncology2405-63082025-03-0151100906Neoadjuvant chemoradiotherapy up-regulates PD-L1 in radioresistant colorectal cancerSung Uk Bae0Hye Won Lee1Jee Young Park2Incheol Seo3Jae-Min Cho4Jin Young Kim5Ju Yup Lee6Yoo Jin Lee7Seong Kyu Baek8Nam Kyu Kim9Sang Jun Byun10Shin Kim11Department of Surgery, School of Medicine, Keimyung University and Dongsan Hospital, Daegu, Republic of Korea; Department of Medicine, The Graduate School, Yonsei University, Seoul, Republic of Korea; Institute of Medical Science & Institute for Cancer Research, Keimyung University, Daegu, Republic of KoreaInstitute of Medical Science & Institute for Cancer Research, Keimyung University, Daegu, Republic of Korea; Department of Pathology, School of Medicine, Keimyung University and Dongsan Hospital, Daegu, Republic of KoreaDepartment of Surgery, School of Medicine, Keimyung University and Dongsan Hospital, Daegu, Republic of Korea; Department of Pathology, School of Medicine, Keimyung University and Dongsan Hospital, Daegu, Republic of Korea; Department of Radiation Oncology, School of Medicine, Keimyung University and Dongsan Hospital, Daegu, Republic of Korea; Department of Immunology, School of Medicine, Keimyung University, Daegu, Republic of KoreaDepartment of Immunology, Kyungpook National University School of Medicine, Daegu, Republic of KoreaDepartment of Surgery, School of Medicine, Keimyung University and Dongsan Hospital, Daegu, Republic of Korea; Department of Pathology, School of Medicine, Keimyung University and Dongsan Hospital, Daegu, Republic of KoreaDivision of Hematology and Oncology, Department of Internal Medicine, School of Medicine, Keimyung University and Dongsan Hospital, Daegu, Republic of KoreaDivision of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Keimyung University and Dongsan Hospital, Daegu, Republic of KoreaDivision of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Keimyung University and Dongsan Hospital, Daegu, Republic of KoreaDepartment of Surgery, School of Medicine, Keimyung University and Dongsan Hospital, Daegu, Republic of KoreaDivision of Colorectal Surgery, Department of Surgery, Severance Hospital, Colorectal Cancer Clinic, Yonsei University College of Medicine, Seoul, Republic of KoreaInstitute of Medical Science & Institute for Cancer Research, Keimyung University, Daegu, Republic of Korea; Department of Radiation Oncology, School of Medicine, Keimyung University and Dongsan Hospital, Daegu, Republic of Korea; Corresponding author at: Department of Radiation Oncology, School of Medicine, Keimyung University and Dongsan Hospital, 1095 Dalgubeol-Daero, Dalseo-Gu, Daegu 42601, Republic of Korea.Institute of Medical Science & Institute for Cancer Research, Keimyung University, Daegu, Republic of Korea; Department of Immunology, School of Medicine, Keimyung University, Daegu, Republic of Korea; Corresponding author at: Department of Immunology, School of Medicine, Keimyung University, 1095 Dalgubeol-Daero, Dalseo-Gu, Daegu 42601, Republic of Korea.Background: Combining radiotherapy (RT) with immune checkpoint inhibitors (ICIs) is a promising strategy that can enhance the therapeutic efficacy of ICIs. However, little is known about RT-induced changes in the expression of immune checkpoints, such as PD-L1, and their clinical implications in colorectal cancer (CRC). This study aimed to investigate the association between responsiveness to RT and changes in PD-L1 expression in human CRC tissue and cell lines. Methods: Tissue specimens from preoperative biopsy via sigmoidoscopy and surgical resection were obtained from 24 patients with locally advanced rectal cancer (LARC) who underwent neoadjuvant chemoradiation therapy (CRT) between August 2016 and December 2017. Immunohistochemistry for PD-L1 in formalin-fixed paraffin-embedded tissue was performed from the endoscopic biopsy and surgical specimens. RNA sequencing was performed using 11 pairs of human LARC tissues before and after irradiation. After exposing human CRC cells to radiation, we investigated changes in the expression levels of PD-L1 and its regulatory signaling pathways. Results: Patients were classified by tumor regression grade into responders (grade 2; 9 patients, 37.5 %) and non-responders (grades 3, 4, or 5; 15 patients, 62.5 %). In the non-responder group, 13 patients had low PD-L1 expression, but neoadjuvant CRT increased PD-L1 expression in 7 patients (53.9 %) (McNemar’s test, p=0.034). CRT up-regulated PD-L1 in non-responder LARC tissues. Similarly, radiation increased PD-L1 in radioresistant DLD-1 cells more than in radiosensitive HCT116 cells, also affecting PD-L1-regulating genes and immune checkpoints in CRC cells. Conventional fractionated radiation treatment further increased PD-L1 in DLD-1 cells compared to HCT116 cells. Conclusions: This study demonstrated that radiation induces an increase in PD-L1 expression, which is more pronounced in radioresistant CRC, proving the theoretical framework for a combined treatment strategy with a PD-L1 blockade for locally advanced rectal cancer.http://www.sciencedirect.com/science/article/pii/S2405630824001836Locally advanced rectal cancerPD-L1ChemoradiotherapyImmune checkpoint inhibitors |
| spellingShingle | Sung Uk Bae Hye Won Lee Jee Young Park Incheol Seo Jae-Min Cho Jin Young Kim Ju Yup Lee Yoo Jin Lee Seong Kyu Baek Nam Kyu Kim Sang Jun Byun Shin Kim Neoadjuvant chemoradiotherapy up-regulates PD-L1 in radioresistant colorectal cancer Clinical and Translational Radiation Oncology Locally advanced rectal cancer PD-L1 Chemoradiotherapy Immune checkpoint inhibitors |
| title | Neoadjuvant chemoradiotherapy up-regulates PD-L1 in radioresistant colorectal cancer |
| title_full | Neoadjuvant chemoradiotherapy up-regulates PD-L1 in radioresistant colorectal cancer |
| title_fullStr | Neoadjuvant chemoradiotherapy up-regulates PD-L1 in radioresistant colorectal cancer |
| title_full_unstemmed | Neoadjuvant chemoradiotherapy up-regulates PD-L1 in radioresistant colorectal cancer |
| title_short | Neoadjuvant chemoradiotherapy up-regulates PD-L1 in radioresistant colorectal cancer |
| title_sort | neoadjuvant chemoradiotherapy up regulates pd l1 in radioresistant colorectal cancer |
| topic | Locally advanced rectal cancer PD-L1 Chemoradiotherapy Immune checkpoint inhibitors |
| url | http://www.sciencedirect.com/science/article/pii/S2405630824001836 |
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