Cancer Immunology, Immunotherapy

, Volume 68, Issue 2, pp 283–296 | Cite as

Upregulation of tumor PD-L1 by neoadjuvant chemoradiotherapy (neoCRT) confers improved survival in patients with lymph node metastasis of locally advanced rectal cancers

  • Shu-Fen Chiang
  • Chih-Yang Huang
  • Tao-Wei Ke
  • Tsung-Wei Chen
  • Yu-Ching Lan
  • Ying-Shu You
  • William Tzu-Liang ChenEmail author
  • K. S. Clifford ChaoEmail author
Original Article


The expression of programmed cell death 1 ligand 1 (PD-L1) and interferon-γ (IFN-γ) is of great interest for the development of chemoradiotherapy and immune checkpoint inhibitor treatments. Patients with nodal metastasis (pN+) tend to have a poor prognosis, even after neoadjuvant chemoradiotherapy (neoCRT) and surgical treatment. In this study, we examined the roles of tumor PD-L1 and IFN-γ before and after neoCRT in locally advanced rectal cancer (LARC) patients. Our results demonstrate that patients with high PD-L1 expression in post-neoCRT tissues exhibit improved 5-year disease-free survival (DFS) and overall survival (OS) compared with those with low PD-L1 expression (p < 0.001). Furthermore, in the pN+ population, patients with high PD-L1 expression in post-neoCRT tissues exhibit improved 5-year DFS and OS. PD-L1 and IFN-γ upregulation increased in tumor tissues after neoCRT, and patients with high PD-L1 and high IFN-γ exhibit improved 5-year DFS and OS (p = 0.04 and p = 0.001, respectively). To the best of our knowledge, this study is the first to demonstrate that PD-L1 upregulation in a pN+ cohort correlates with improved prognosis, which is similar to that in patients without nodal metastasis. Moreover, this study verified that PD-L1 and IFN-γ were upregulated by neoCRT treatment in LARC patients and demonstrated that neoCRT may be useful not only for immune checkpoint inhibitor treatment but also for reinvigorating preexisting anti-cancer immunity.


Programmed death ligand 1 Interferon-γ Locally advanced rectal cancer Lymph node metastasis Neoadjuvant chemoradiotherapy 



Colorectal cancer


Danger-associated molecular patterns


Disease-free survival


Immune checkpoint blockade


Immunogenic cell death




Locally advanced rectal cancer


Microsatellite instability


Neoadjuvant chemoradiotherapy


Overall survival


Pathologic complete response


Programmed cell death 1 receptor


Programmed cell death 1 ligand 1

pN stage

Pathologic lymph node stage


Tumor-infiltrating lymphocytes


Tissue microarray


Tumor regression grade


Author contributions

C-YH and S-FC conducted and performed the experiments; WT-LC, T-WK and T-WC enrolled the LARC patients and performed IHC evaluation; Y-SY and Y-CL performed the statistical analysis; S-FC and KSCC supervised this study; C-YH, S-FC, and KSCC analyzed the data and wrote the manuscript. All authors read and approved the final manuscript version.


This study was supported by grants from China Medical University Hospital [DMR-107-103 (Taiwan) and DMR-CELL-17022 (Taiwan)], Ministry of Science and Technology (MOST 107-2314-B-039 -027 -MY3, Taiwan), Ministry of Health, and Welfare (MOHW107-TDU-B-212-123004, Taiwan), and Health and welfare surcharge of tobacco products, China Medical University Hospital Cancer Research Center of Excellence (MOHW107-TDU-B-212-114024, Taiwan).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

262_2018_2275_MOESM1_ESM.pdf (301 kb)
Supplementary material 1 (PDF 300 KB)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Cancer Center, China Medical University HospitalChina Medical UniversityTaichungTaiwan
  2. 2.Translation Research Core, Medical University HospitalChina Medical UniversityTaichungTaiwan
  3. 3.Department of nutritionHungKuang UniversityTaichungTaiwan
  4. 4.Department of Colorectal Surgery, China Medical University HospitalChina Medical UniversityTaichungTaiwan
  5. 5.Department of Pathology, China Medical University HospitalChina Medical UniversityTaichungTaiwan
  6. 6.Graduate Institute of Biomedical ScienceChina Medical UniversityTaichungTaiwan
  7. 7.Department of Health Risk ManagementChina Medical UniversityTaichungTaiwan

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