Cancer Immunology, Immunotherapy

, Volume 67, Issue 4, pp 551–562 | Cite as

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

  • Chih-Yang Huang
  • Shu-Fen Chiang
  • Tao-Wei Ke
  • Tsung-Wei Chen
  • Yu-Ching Lan
  • Ying-Shu You
  • An-Cheng Shiau
  • William Tzu-Liang Chen
  • K. S. Clifford Chao
Original Article


Rectal cancer, which comprises 30% of all colorectal cancer cases, is one of the most common forms of cancer in the world. Patients with locally advanced rectal cancer (LARC) are often treated with neoadjuvant chemoradiotherapy (neoCRT) followed by surgery. However, after neoCRT treatment, approximately one-third of the patients progress to local recurrence or distant metastasis. In these studies, we found that patients with tumors that exhibited cytosolic HMGB1(Cyto-HMGB1) translocation and/or the presence of PD-1+ tumor-infiltrating lymphocytes (TILs) before treatment had a better clinical outcome. The better outcome is likely due to the release of HMGB1, which triggers the maturation of dendritic cells (DCs) via TLR4 activation, and the subsequent recruitment of PD-1+ tumor-infiltrating lymphocytes to the tumor site, where they participate in immune-scavenging. In conclusion, our results provide evidence that cyto-HMGB1 and/or PD-1+TIL are not only predictive biomarkers before treatment, but they can also potentially designate patients for personalized oncological management including immunotherapy.





Area under curve


Colorectal cancer


Damage-associated molecular pattern molecules


Dendritic cell


Disease-free survival


Distant metastasis


High-mobility group box 1


Immunogenic cell death


Locally advanced rectal cancer


Local recurrence


Neoadjuvant chemoradiotherapy


Overall survival


Pathologic complete response


Programmed death 1 receptor

pN stage

Pathologic lymph node stage


Pathologic partial response


Receiver operating characteristic


Tumor-infiltrating lymphocytes


Toll-like receptor 4


Tissue microarray


Tumor regression grade



We are grateful for the tissue microarray (TMA) support from the Translation Research Core, China Medical University Hospital. Ms. Vicky Lin assisted in the preparation of the manuscript.

Author contributions

Chih-Yang Huang and Shu-Fen Chiang conducted and performed the experiments; William Tzu-Liang Chen, Tao-Wei Ke and Tsung-Wei Chen participated in the collection and IHC evaluation of the LARC patients; Yu-Ching Lan and Ying-Shu You performed the statistical analysis; An-Cheng Shiau performed radical experiments; Shu-Fen Chiang, William Tzu-Liang Chen and K. S. Clifford Chao supervised this study; Chih-Yang Huang, Shu-Fen Chiang and K. S. Clifford Chao analyzed the data and wrote the manuscript.

Compliance with ethical standards

Funding resource

This study is supported in part by China Medical University Hospital (DMR-106-107 and DMR-CELL-17,018), Ministry of Science and Technology (MOST106-2314-B-039-005) and Ministry of Health, and Welfare (MOHW106-TDU-B-212-113004).

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval and ethical standards

This study was reviewed and approved by the Internal Review Board (IRB) of China Medical University Hospital [Protocol number: CMUH105-REC2-072].

Informed consent

Informed consents were obtained from all participants in the study.

Supplementary material

262_2017_2109_MOESM1_ESM.pdf (482 kb)
Supplementary material 1 (PDF 482 KB)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2017

Authors and Affiliations

  • Chih-Yang Huang
    • 1
  • Shu-Fen Chiang
    • 2
  • Tao-Wei Ke
    • 3
  • Tsung-Wei Chen
    • 4
  • Yu-Ching Lan
    • 5
  • Ying-Shu You
    • 2
  • An-Cheng Shiau
    • 2
  • William Tzu-Liang Chen
    • 3
  • K. S. Clifford Chao
    • 2
  1. 1.Translation Research Core, China Medical University HospitalChina Medical UniversityTaichungTaiwan, ROC
  2. 2.Cancer Center Building, Cancer Center, China Medical University HospitalChina Medical UniversityTaichungTaiwan, ROC
  3. 3.Department of Colorectal Surgery, China Medical University HospitalChina Medical UniversityTaichungTaiwan, ROC
  4. 4.Department of Pathology, China Medical University HospitalChina Medical UniversityTaichungTaiwan, ROC
  5. 5.Department of Health Risk ManagementChina Medical UniversityTaichungTaiwan, ROC

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