Prognostic relevance of programmed cell death-ligand 1 expression and CD8+ TILs in rectal cancer patients before and after neoadjuvant chemoradiotherapy
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Radiotherapy has been recently reported to boost the therapeutic response of immune checkpoint blockade (ICB); however, few studies have focused on programmed cell death-ligand 1 (PD-L1) expression in locally advanced rectal cancer (LARC) patients who receive preoperative neoadjuvant chemoradiotherapy (neoCRT). The aim of the present study was to investigate the PD-L1 expression status and CD8+ intra-tumoral infiltrating lymphocytes (TILs) before and after neoCRT and its association with clinicopathological characteristics in rectal cancer.
Materials and methods
Immunostainings of PD-L1 and CD8+ TILs were performed in 112 pair-matched LARC patients treated by neoCRT. Tumor PD-L1 expression and CD8+ TILs within the tumor microenvironment before and after neoCRT were evaluated via immunohistochemistry.
High tumor PD-L1 expression was significantly increased from 50 to 63%, and high CD8+ TILs counts were also slightly increased from 32 to 35% after neoCRT treatment. High tumor PD-L1 before and after neoCRT was associated with improved disease-free survival (DFS, pre-neoCRT: p = 0.003 and post-neoCRT: p = 0.003) and overall survival (OS, pre-neoCRT: p = 0.045 and post-neoCRT: p = 0.0001). High CD8+ TILs before neoCRT was associated with improved DFS (p = 0.057), and it was significantly associated with improved DFS after neoCRT (p = 0.039). Patients with high tumor PD-L1 and CD8+ TILs before and after neoCRT were significantly associated with improved DFS (pre-neoCRT: p = 0.004 and post-neoCRT: p = 0.006).
The present results provide evidence that tumor PD-L1 expression and recruitment of CD8+ TILs within the tumor microenvironment were increased by neoCRT treatment. Tumor PD-L1 and CD8+ TILs are prognostic biomarkers for the survival of LARC patients treated with neoCRT.
KeywordsNeoadjuvant chemoradiotherapy Programmed cell death 1 ligand 1 CD8 Tumor-infiltrating lymphocyte Locally advanced rectal cancer
We are grateful for the tissue microarray support from the Translation Research Core, China Medical University Hospital. This study is supported in part by China Medical University Hospital (DMR-107-061), Ministry of Science and Technology Ministry of Science and Technology (MOST107-2314-B-039-027-MY3 and MOST107-2314-B-039-057-MY3, Taiwan), and Ministry of Health and Welfare (MOHW107-TDU-B-212-123004, Taiwan), Health and welfare surcharge of tobacco products, China Medical University Hospital Cancer Research Center of Excellence (MOHW108-TDU-B-212-124024, Taiwan).
T-WC, S-FC and KC-YH conducted and performed the experiments; WT-LC, T-WK and T-WC enrolled the LARC patients and performed IHC evaluation; S-FC and KSCC supervised this study; S-FC, and KSCC analyzed the data and wrote the manuscript.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
This study was reviewed and approved by the Internal Review Board (IRB) of China Medical University Hospital [Protocol number: CMUH105-REC2-072].
Informed consents were obtained from all participants in the study.
- Gameiro SR, Jammeh ML, Wattenberg MM, Tsang KY, Ferrone S, Hodge JW (2014) Radiation-induced immunogenic modulation of tumor enhances antigen processing and calreticulin exposure, resulting in enhanced T-cell killing. Oncotarget 5:403–416. https://doi.org/10.18632/oncotarget.1719 CrossRefGoogle Scholar
- Hirano F et al (2005) Blockade of B7-H1 and PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer Res 65:1089–1096Google Scholar
- Huang CY et al (2018b) Cytosolic high-mobility group box protein 1 (HMGB1) and/or PD-1 + TILs in the tumor microenvironment may be contributing prognostic biomarkers for patients with locally advanced rectal cancer who have undergone neoadjuvant chemoradiotherapy. Cancer Immunol Immunother 67:551–562. https://doi.org/10.1007/s00262-017-2109-5 CrossRefGoogle Scholar
- Keir ME, Butte MJ, Freeman GJ, Sharpe AH (2008) PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 26:677–704. https://doi.org/10.1146/annurev.immunol.26.021607.090331 CrossRefGoogle Scholar
- Lim YJ et al (2017) Chemoradiation-induced alteration of programmed death-ligand 1 and CD8+ tumor-infiltrating lymphocytes identified patients with poor prognosis in rectal cancer: a matched comparison analysis. Int J Radiat Oncol Biol Phys 99:1216–1224. https://doi.org/10.1016/j.ijrobp.2017.07.004 CrossRefGoogle Scholar
- Sauer R et al (2012) Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: results of the German CAO/ARO/AIO-94 randomized phase III trial after a median follow-up of 11 years. J Clin Oncol 30:1926–1933. https://doi.org/10.1200/JCO.2011.40.1836 CrossRefGoogle Scholar