High expression of carcinoembryonic antigen and telomerase reverse transcriptase in circulating tumor cells is associated with poor clinical response to the immune checkpoint inhibitor nivolumab

Bao,Halin; Bai,Tuya; Takata,Koji; Yokobori,Takehiko; Ohnaga,Takashi; Hisada,Takeshi; Maeno,Toshitaka; Bao,Pinjie; Yoshida,Tomonori; Kumakura,Yuji; Honjo,Hiroaki; Sakai,Makoto; Sohda,Makoto; Fukuchi,Minoru; Altan,Bolag; Handa,Tadashi; Ide,Munenori; Miyazaki,Tatsuya; Ogata,Kyoichi; Oyama,Tetsunari; Shimizu,Kimihiro; Mogi,Akira; Asao,Takayuki; Shirabe,Ken; Kuwano,Hiroyuki; Kaira,Kyoichi

doi:10.3892/ol.2017.7671

High expression of carcinoembryonic antigen and telomerase reverse transcriptase in circulating tumor cells is associated with poor clinical response to the immune checkpoint inhibitor nivolumab

Authors:
- Halin Bao
- Tuya Bai
- Koji Takata
- Takehiko Yokobori
- Takashi Ohnaga
- Takeshi Hisada
- Toshitaka Maeno
- Pinjie Bao
- Tomonori Yoshida
- Yuji Kumakura
- Hiroaki Honjo
- Makoto Sakai
- Makoto Sohda
- Minoru Fukuchi
- Bolag Altan
- Tadashi Handa
- Munenori Ide
- Tatsuya Miyazaki
- Kyoichi Ogata
- Tetsunari Oyama
- Kimihiro Shimizu
- Akira Mogi
- Takayuki Asao
- Ken Shirabe
- Hiroyuki Kuwano
- Kyoichi Kaira
View Affiliations

Affiliations: Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma 371‑8511, Japan, Toyama Industrial Technology Center, Takaoka, Toyama 933‑0981, Japan, Department of Respiratory Medicine, Graduate School of Medicine, Gunma University, Maebashi, Gunma 371‑8511, Japan, Department of Oncology Clinical Development, Graduate School of Medicine, Gunma University, Maebashi, Gunma 371‑8511, Japan, Department of Diagnostic Pathology, Graduate School of Medicine, Gunma University, Maebashi, Gunma 371‑8511, Japan, Integrative Center of General Surgery, Gunma University Hospital, Maebashi, Gunma, 371-8510, Japan, Big Data Center for Integrative Analysis, Gunma University Initiative for Advance Research, Maebashi, Gunma 371‑8511, Japan
Published online on: December 20, 2017 https://doi.org/10.3892/ol.2017.7671
Pages: 3061-3067
Copyright: © Bao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The present study aimed to enrich circulating tumor cells (CTCs) from blood samples using a new size‑sorting CTC chip. The present study also set out to identify a blood sensitivity marker for the immune checkpoint inhibitor nivolumab in patients with advanced, pre‑treatment lung cancer. The CTC sorting efficacy of the chip was investigated and the large cell fraction of blood samples from 15 patients with pre‑treatment lung cancer who were later administered nivolumab were purified. The expression levels of carcinoembryonic antigen (CEA), human Telomerase Reverse Transcriptase (hTERT), cytokeratin19 (CK19), and programmed death ligand‑1 (PD‑L1) were investigated to clarify the association between these CTC markers and the clinical response to nivolumab. The CTC chip effectively enriched cells from lung cancer cell line PC‑9. The large cell fraction had a high expression of CEA and hTERT, with the former being significantly associated with the clinical response to nivolumab. The expression of CEA and hTERT in CTCs derived from the blood of a patient with lung cancer were also validated. The evaluation of CEA and possibly hTERT in CTCs collected by the CTC chip may represent a promising predictive blood marker for sensitivity to nivolumab. To the best of our knowledge this is the first report to describe the predictive CTC marker for nivolumab in pre‑treatment patients.

View Figures

View References

1	Sharma P and Allison JP: The future of immune checkpoint therapy. Science. 348:56–61. 2015. View Article : Google Scholar : PubMed/NCBI
2	Ma W, Gilligan BM, Yuan J and Li T: Current status and perspectives in translational biomarker research for PD-1/PD-L1 immune checkpoint blockade therapy. J Hematol Oncol. 9:472016. View Article : Google Scholar : PubMed/NCBI
3	Meng X, Huang Z, Teng F, Xing L and Yu J: Predictive biomarkers in PD-1/PD-L1 checkpoint blockade immunotherapy. Cancer Treat Rev. 41:868–876. 2015. View Article : Google Scholar : PubMed/NCBI
4	Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, et al: Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 373:1627–1639. 2015. View Article : Google Scholar : PubMed/NCBI
5	Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E, et al: Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 372:320–330. 2015. View Article : Google Scholar : PubMed/NCBI
6	Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Procopio G, Plimack ER, et al: Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 373:1803–1813. 2015. View Article : Google Scholar : PubMed/NCBI
7	Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, Skora AD, Luber BS, Azad NS, Laheru D, et al: PD-1 Blockade in tumors with mismatch-repair deficiency. N Engl J Med. 372:2509–2520. 2015. View Article : Google Scholar : PubMed/NCBI
8	Pantel K and Alix-Panabières C: Circulating tumour cells in cancer patients: Challenges and perspectives. Trends Mol Med. 16:398–406. 2010. View Article : Google Scholar : PubMed/NCBI
9	Alix-Panabières C and Pantel K: Challenges in circulating tumour cell research. Nat Rev Cancer. 14:623–631. 2014. View Article : Google Scholar : PubMed/NCBI
10	Sun YF, Yang XR, Zhou J, Qiu SJ, Fan J and Xu Y: Circulating tumor cells: Advances in detection methods, biological issues, and clinical relevance. J Cancer Res Clin Oncol. 137:1151–1173. 2011. View Article : Google Scholar : PubMed/NCBI
11	Nagrath S, Sequist LV, Maheswaran S, Bell DW, Irimia D, Ulkus L, Smith MR, Kwak EL, Digumarthy S, Muzikansky A, et al: Isolation of rare circulating tumour cells in cancer patients by microchip technology. Nature. 450:1235–1239. 2007. View Article : Google Scholar : PubMed/NCBI
12	Dong Y, Skelley AM, Merdek KD, Sprott KM, Jiang C, Pierceall WE, Lin J, Stocum M, Carney WP and Smirnov DA: Microfluidics and circulating tumor cells. J Mol Diagn. 15:149–157. 2013. View Article : Google Scholar : PubMed/NCBI
13	Seal SH: A sieve for the isolation of cancer cells and other large cells from the blood. Cancer. 17:637–642. 1964. View Article : Google Scholar : PubMed/NCBI
14	Yu Y, Xu G, Cao J, Jin S, Man Y and Shang L: Combination of four gene markers to detect circulating tumor cells in the peripheral blood of patients with advanced lung adenocarcinoma using real-time PCR. Oncol Lett. 5:1400–1406. 2013. View Article : Google Scholar : PubMed/NCBI
15	Tanaka F, Yoneda K and Hasegawa S: Circulating tumor cells (CTCs) in lung cancer: Current status and future perspectives. Lung Cancer (Auckl). 1:77–84. 2010.PubMed/NCBI
16	Mazel M, Jacot W, Pantel K, Bartkowiak K, Topart D, Cayrefourcq L, Rossille D, Maudelonde T, Fest T and Alix-Panabières C: Frequent expression of PD-L1 on circulating breast cancer cells. Mol Oncol. 9:1773–1782. 2015. View Article : Google Scholar : PubMed/NCBI
17	Huang LR, Cox EC, Austin RH and Sturm JC: Continuous particle separation through deterministic lateral displacement. Science. 304:987–990. 2004. View Article : Google Scholar : PubMed/NCBI
18	Ohnaga T, Shimada Y, Moriyama M, Kishi H, Obata T, Takata K, Okumura T, Nagata T, Muraguchi A and Tsukada K: Polymeric microfluidic devices exhibiting sufficient capture of cancer cell line for isolation of circulating tumor cells. Biomed Microdevices. 15:611–616. 2013. View Article : Google Scholar : PubMed/NCBI
19	Yokobori T, Iinuma H, Shimamura T, Imoto S, Sugimachi K, Ishii H, Iwatsuki M, Ota D, Ohkuma M, Iwaya T, et al: Plastin3 is a novel marker for circulating tumor cells undergoing the epithelial-mesenchymal transition and is associated with colorectal cancer prognosis. Cancer Res. 73:2059–2069. 2013. View Article : Google Scholar : PubMed/NCBI
20	Hanahan D and Weinberg RA: Hallmarks of cancer: The next generation. Cell. 144:646–674. 2011. View Article : Google Scholar : PubMed/NCBI
21	Beauchemin N and Arabzadeh A: Carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) in cancer progression and metastasis. Cancer Metastasis Rev. 32:643–671. 2013. View Article : Google Scholar : PubMed/NCBI
22	Cong Y and Shay JW: Actions of human telomerase beyond telomeres. Cell Res. 18:725–732. 2008. View Article : Google Scholar : PubMed/NCBI
23	Alix-Panabières C and Pantel K: Technologies for detection of circulating tumor cells: Facts and vision. Lab Chip. 14:57–62. 2014. View Article : Google Scholar : PubMed/NCBI
24	Vona G, Sabile A, Louha M, Sitruk V, Romana S, Schütze K, Capron F, Franco D, Pazzagli M, Vekemans M, et al: Isolation by size of epithelial tumor cells: A new method for the immunomorphological and molecular characterization of circulating tumor cells. Am J Pathol. 156:57–63. 2000. View Article : Google Scholar : PubMed/NCBI
25	Busch R, Cesar D, Higuera-Alhino D, Gee T, Hellerstein MK and McCune JM: Isolation of peripheral blood CD4(+) T cells using RosetteSep and MACS for studies of DNA turnover by deuterium labeling. J Immunol Methods. 286:97–109. 2004. View Article : Google Scholar : PubMed/NCBI
26	Polyak K and Weinberg RA: Transitions between epithelial and mesenchymal states: Acquisition of malignant and stem cell traits. Nat Rev Cancer. 9:265–273. 2009. View Article : Google Scholar : PubMed/NCBI
27	Ohnaga T, Shimada Y, Takata K, Obata T, Okumura T, Nagata T, Kishi H, Muraguchi A and Tsukada K: Capture of esophageal and breast cancer cells with polymeric microfluidic devices for CTC isolation. Mol Clin Oncol. 4:599–602. 2016. View Article : Google Scholar : PubMed/NCBI