PD-L1 is a double-edged sword in colorectal cancer: the prognostic value of PD-L1 depends on the cell type expressing PD-L1

Ho, Hsiang-Ling; Chou, Teh-Ying; Yang, Shung-Haur; Jiang, Jeng-Kai; Chen, Wei-Shone; Chao, Yee; Teng, Hao-Wei

doi:10.1007/s00432-019-02942-y

Original Article – Cancer Research
Published: 25 May 2019

PD-L1 is a double-edged sword in colorectal cancer: the prognostic value of PD-L1 depends on the cell type expressing PD-L1

Hsiang-Ling Ho^1,2,
Teh-Ying Chou^1,2,3,
Shung-Haur Yang^5,6,7,
Jeng-Kai Jiang^5,6,
Wei-Shone Chen^5,6,
Yee Chao^4,5 &
Hao-Wei Teng ORCID: orcid.org/0000-0001-8480-3422^3,4,5

Journal of Cancer Research and Clinical Oncology volume 145, pages 1785–1794 (2019)Cite this article

479 Accesses
11 Citations
Metrics details

Abstract

Purpose

To investigate the associations between programmed cell death ligand-1 (PD-L1) on tumor cells (TCs) or PD-L1 on tumor-infiltrating immune cells (TIICs) and the microsatellite instability (MSI) status in colorectal cancer (CRC).

Methods

In total, 238 CRC patients were enrolled. PD-L1 expression and MSI status were studied by immunohistochemical staining and polymerase chain reaction. The χ² test was used to compare characteristics. The Kaplan–Meier method was used for survival analysis. Cox proportional hazards models were used to determine the prognostic influence of clinicopathological factors.

Results

Eighteen patients (7.6%) were had MSI-high (MSI-H) CRC. The number of patients with PD-L1 expression on TCs, stromal TIICs and intraepithelial TIICs was 13 (5.5%), 64 (26.9%) and 45 (18.9%), respectively. The MSI-H phenotype was significantly associated with younger age, right sidedness, mucinous component, high grade, stromal TIICs expressing PD-L1 (P = 0.042) and intraepithelial TIICs expressing PD-L1 (P < 0.001), but not TCs expressing PD-L1. PD-L1-expressing TCs were an independent marker of poor prognosis [hazard ratio (HR) = 3.387, P = 0.003], and PD-L1-expressing stromal TIICs were an independent marker of good prognosis (HR = 0.551, P < 0.001).

Conclusions

PD-L1-expressing TCs were a marker of poor prognosis; in contrast, PD-L1-expressing TIICs were a marker of good prognosis. The MSI-H phenotype was associated with the presence of PD-L1-expressing TIICs, but not of PD-L1-expressing TCs.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

References

Bacher JW et al (2015) Improved detection of microsatellite instability in early colorectal lesions. PLoS One 10:e0132727. https://doi.org/10.1371/journal.pone.0132727
Article CAS PubMed PubMed Central Google Scholar
Barber DL et al (2006) Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439:682–687. https://doi.org/10.1038/nature04444
Article CAS Google Scholar
Brenner H, Kloor M, Pox CP (2014) Colorectal cancer. Lancet 383:1490–1502. https://doi.org/10.1016/S0140-6736(13)61649-9
Article Google Scholar
Callea M et al (2015) Differential expression of PD-L1 between primary and metastatic sites in clear-cell renal cell carcinoma. Cancer Immunol Res 3:1158–1164. https://doi.org/10.1158/2326-6066.cir-15-0043
Article CAS PubMed PubMed Central Google Scholar
Droeser RA et al (2013) Clinical impact of programmed cell death ligand 1 expression in colorectal cancer. Eur J Cancer 49:2233–2242. https://doi.org/10.1016/j.ejca.2013.02.015
Article CAS Google Scholar
El Jabbour T et al (2018) PD-L1 protein expression in tumour cells and immune cells in mismatch repair protein-deficient and -proficient colorectal cancer: the foundation study using the SP142 antibody and whole section immunohistochemistry. J Clin Pathol 71:46–51. https://doi.org/10.1136/jclinpath-2017-204525
Article CAS PubMed Google Scholar
Elez E, Argiles G, Tabernero J (2015) First-line treatment of metastatic colorectal cancer: interpreting FIRE-3, PEAK, and CALGB/SWOG 80405. Curr Treat Options Oncol 16:52. https://doi.org/10.1007/s11864-015-0369-x
Article PubMed Google Scholar
Haggar FA, Boushey RP (2009) Colorectal cancer epidemiology: incidence, mortality, survival, and risk factors. Clin Colon Rectal Surg 22:191–197. https://doi.org/10.1055/s-0029-1242458
Article PubMed PubMed Central Google Scholar
Hamada T et al (2018) TIME (Tumor Immunity in the MicroEnvironment) classification based on tumor CD274 (PD-L1) expression status and tumor-infiltrating lymphocytes in colorectal carcinomas. Oncoimmunology 7:e1442999. https://doi.org/10.1080/2162402x.2018.1442999
Article CAS PubMed PubMed Central Google Scholar
Hellmann MD et al (2018) Nivolumab plus Ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med 378:2093–2104. https://doi.org/10.1056/NEJMoa1801946
Article CAS PubMed Google Scholar
Herbst RS et al (2016) Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 387:1540–1550. https://doi.org/10.1016/s0140-6736(15)01281-7
Article CAS PubMed Google Scholar
Ilie M et al (2016) Comparative study of the PD-L1 status between surgically resected specimens and matched biopsies of NSCLC patients reveal major discordances: a potential issue for anti-PD-L1 therapeutic strategies. Ann Oncol 27:147–153. https://doi.org/10.1093/annonc/mdv489
Article CAS PubMed Google Scholar
Inaguma S, Lasota J, Wang Z, Felisiak-Golabek A, Ikeda H, Miettinen M (2017) Clinicopathologic profile, immunophenotype, and genotype of CD274 (PD-L1)-positive colorectal carcinomas. Mod Pathol 30:278–285. https://doi.org/10.1038/modpathol.2016.185
Article CAS PubMed Google Scholar
Jakubowska K, Kisielewski W, Kanczuga-Koda L, Koda M, Famulski W (2017) Stromal and intraepithelial tumor-infiltrating lymphocytes in colorectal carcinoma Oncol Lett 14:6421–6432. https://doi.org/10.3892/ol.2017.7013
CAS Article PubMed Google Scholar
Kassem A, Schopflin A, Diaz C, Weyers W, Stickeler E, Werner M, Zur Hausen A (2008) Frequent detection of Merkel cell polyomavirus in human Merkel cell carcinomas and identification of a unique deletion in the VP1 gene. Cancer Res 68:5009–5013. https://doi.org/10.1158/0008-5472.can-08-0949
Article CAS PubMed Google Scholar
Lawrence MS et al (2013) Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 499:214–218. https://doi.org/10.1038/nature12213
Article CAS PubMed PubMed Central Google Scholar
Le DT et al (2015) PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med 372:2509–2520. https://doi.org/10.1056/nejmoa1500596
Article CAS PubMed PubMed Central Google Scholar
Lee KS et al (2017) Prognostic implication of CD274 (PD-L1) protein expression in tumor-infiltrating immune cells for microsatellite unstable and stable colorectal cancer. Cancer Immunol Immunother 66:927–939. https://doi.org/10.1007/s00262-017-1999-6
Article CAS Google Scholar
Lee KS, Kim BH, Oh HK, Kim DW, Kang SB, Kim H, Shin E (2018a) PD-L1 protein expression and CD274/PD-L1 gene amplification in colorectal cancer: implications for prognosis. Cancer Sci. https://doi.org/10.1111/cas.13716
Article PubMed PubMed Central Google Scholar
Lee SJ et al (2018b) CD274, LAG3, and IDO1 expressions in tumor-infiltrating immune cells as prognostic biomarker for patients with MSI-high colon cancer. J Cancer Res Clin Oncol 144:1005–1014. https://doi.org/10.1007/s00432-018-2620-x
Article CAS PubMed Google Scholar
Li Y et al (2016) Prognostic impact of programed cell death-1 (PD-1) and PD-ligand 1 (PD-L1) expression in cancer cells and tumor infiltrating lymphocytes in colorectal cancer. Mol Cancer 15:55. https://doi.org/10.1186/s12943-016-0539-x
Article PubMed PubMed Central Google Scholar
Madore J et al (2015) PD-L1 expression in melanoma shows marked heterogeneity within and between patients: implications for anti-PD-1/PD-L1 clinical trials. Pigment Cell Melanoma Res 28:245–253. https://doi.org/10.1111/pcmr.12340
Article CAS Google Scholar
Overman MJ et al (2017) Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol 18:1182–1191. https://doi.org/10.1016/s1470-2045(17)30422-9
Article CAS PubMed PubMed Central Google Scholar
Postow MA, Callahan MK, Wolchok JD (2015) Immune checkpoint blockade in cancer therapy. J Clin Oncol 33:1974–1982. https://doi.org/10.1200/JCO.2014.59.4358
Article CAS PubMed PubMed Central Google Scholar
Rimm DL et al (2017) A Prospective, multi-institutional, pathologist-based assessment of 4 immunohistochemistry assays for PD-L1 expression in non-small cell lung cancer. JAMA Oncol 3:1051–1058. https://doi.org/10.1001/jamaoncol.2017.0013
Article PubMed PubMed Central Google Scholar
Robert C et al (2015) Pembrolizumab versus Ipilimumab in advanced melanoma. N Engl J Med 372:2521–2532. https://doi.org/10.1056/NEJMoa1503093
Article CAS PubMed Google Scholar
Salgado R et al (2015) The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol 26:259–271. https://doi.org/10.1093/annonc/mdu450
Article CAS Google Scholar
Shitara K et al (2018) Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial. Lancet 392:123–133. https://doi.org/10.1016/s0140-6736(18)31257-1
Article CAS PubMed Google Scholar
Spranger S, Spaapen RM, Zha Y, Williams J, Meng Y, Ha TT, Gajewski TF (2013) Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells. Sci Transl Med 5:200ra116. https://doi.org/10.1126/scitranslmed.3006504
Article CAS PubMed PubMed Central Google Scholar
Tauriello DVF et al (2018) TGFbeta drives immune evasion in genetically reconstituted colon cancer metastasis. Nature 554:538–543. https://doi.org/10.1038/nature25492
Article CAS Google Scholar
Vilar E, Gruber SB (2010) Microsatellite instability in colorectal cancer-the stable evidence. Nat Rev Clin Oncol 7:153–162. https://doi.org/10.1038/nrclinonc.2009.237
Article CAS PubMed PubMed Central Google Scholar
Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA Jr, Kinzler KW (2013) Cancer genome landscapes. Science 339:1546–1558. https://doi.org/10.1126/science.1235122
Article CAS PubMed PubMed Central Google Scholar
Whitmire JK, Tan JT, Whitton JL (2005) Interferon-gamma acts directly on CD8 + T cells to increase their abundance during virus infection. J Exp Med 201:1053–1059. https://doi.org/10.1084/jem.20041463
Article CAS PubMed PubMed Central Google Scholar
Xiao Y, Freeman GJ (2015) The microsatellite instable subset of colorectal cancer is a particularly good candidate for checkpoint blockade. Immunother Cancer Discov 5:16–18. https://doi.org/10.1158/2159-8290.CD-14-1397
Article CAS Google Scholar
Xie Z et al (2009) Intrahepatic PD-1/PD-L1 up-regulation closely correlates with inflammation and virus replication in patients with chronic HBV infection. Immunol Invest 38:624–638
Article CAS PubMed Google Scholar
Yu Y (2018) Molecular classification and precision therapy of cancer: immune checkpoint inhibitors. Front Med 12:229–235. https://doi.org/10.1007/s11684-017-0581-0
Article PubMed Google Scholar

Download references

Acknowledgements

We are thankful for grants from the Taiwan Clinical Oncology Research Foundation, Ministry of Health and Welfare, Taiwan (MOHW107-TDU-B-211-114019), Taipei Veterans General Hospital (107DHA0100381 and 108DHA0100103) and Yen Tjing Ling Medical Foundation (CI-108-19). The authors would like to acknowledge the support from the Biobank of Taipei Veterans General Hospital and Precision Medicine Envision Project, Taipei Veterans General Hospital.

Funding

This study was funded by grants from the Taiwan Clinical Oncology Research Foundation, Ministry of Health and Welfare, Taiwan (MOHW107-TDU-B-211-114019), Taipei Veterans General Hospital (107DHA0100381 and 108DHA0100103) and Yen Tjing Ling Medical Foundation (CI-108-19).

Author information

Affiliations

Division of Molecular Pathology, Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
Hsiang-Ling Ho & Teh-Ying Chou
Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei, Taiwan
Hsiang-Ling Ho & Teh-Ying Chou
Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
Teh-Ying Chou & Hao-Wei Teng
Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Road, Taipei 112, Taiwan
Yee Chao & Hao-Wei Teng
School of Medicine, National Yang-Ming University, No. 155, Sec. 2, Linong Street, Taipei 112, Taiwan
Shung-Haur Yang, Jeng-Kai Jiang, Wei-Shone Chen, Yee Chao & Hao-Wei Teng
Division of Colon and Rectum Surgery, Department of Surgery, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Road, Taipei 112, Taiwan
Shung-Haur Yang, Jeng-Kai Jiang & Wei-Shone Chen
Department of Surgery, National Yang-Ming University Hospital, Yilan, Taiwan
Shung-Haur Yang

Authors

Hsiang-Ling Ho
View author publications
You can also search for this author in PubMed Google Scholar
Teh-Ying Chou
View author publications
You can also search for this author in PubMed Google Scholar
Shung-Haur Yang
View author publications
You can also search for this author in PubMed Google Scholar
Jeng-Kai Jiang
View author publications
You can also search for this author in PubMed Google Scholar
Wei-Shone Chen
View author publications
You can also search for this author in PubMed Google Scholar
Yee Chao
View author publications
You can also search for this author in PubMed Google Scholar
Hao-Wei Teng
View author publications
You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hao-Wei Teng.

Ethics declarations

Conflict of interest

The authors Hsiang-Ling Ho, Teh-Ying Chou, Shung-Haur Yang, Jeng-Kai Jiang, Wei-Shone Chen, Yee Chao, and Hao-Wei Teng declare that they have no conflict of interest.

Ethical approval

This retrospective study was conducted using data from Taipei Veterans General Hospital, Taipei, Taiwan and under the guidelines of the Declarations of Helsinki; it was approved by the Human Subjects Protection Offices at Taipei Veterans General Hospital. The medical residual samples of the patients with CRC were acquired from the residual sample bank of Taipei Veterans General Hospital. VGHIRB waived the requirement for the use of an informed consent form.

Informed consent

Informed consent was not obtained prior to analysis in this study (VGHIRB waived the requirement for the use of an inform consent form).

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Ho, HL., Chou, TY., Yang, SH. et al. PD-L1 is a double-edged sword in colorectal cancer: the prognostic value of PD-L1 depends on the cell type expressing PD-L1. J Cancer Res Clin Oncol 145, 1785–1794 (2019). https://doi.org/10.1007/s00432-019-02942-y

Download citation

Received: 12 February 2019
Accepted: 21 May 2019
Published: 25 May 2019
Issue Date: 01 July 2019
DOI: https://doi.org/10.1007/s00432-019-02942-y

Keywords

Colorectal cancer
Microsatellite instability
PD-L1
Immunotherapy