Open Access

Phospho‑STAT1 expression as a potential biomarker for anti‑PD‑1/anti‑PD‑L1 immunotherapy for breast cancer

  • Authors:
    • Yuko Nakayama
    • Kosaku Mimura
    • Tomoaki Tamaki
    • Kensuke Shiraishi
    • Ley‑Fang Kua
    • Vivien Koh
    • Masato Ohmori
    • Ayako Kimura
    • Shingo Inoue
    • Hirokazu Okayama
    • Yoshiyuki Suzuki
    • Tadao Nakazawa
    • Daisuke Ichikawa
    • Koji Kono
  • View Affiliations

  • Published online on: April 10, 2019     https://doi.org/10.3892/ijo.2019.4779
  • Pages: 2030-2038
  • Copyright: © Nakayama et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 4.0].

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Abstract

In the present study, we evaluated the mechanisms of programmed death ligand 1 (PD‑L1) expression in the breast cancer microenvironment, focusing on the role of interferon‑γ (IFN‑γ), and the clinical indications for anti‑programmed cell death 1 (PD‑1) /anti‑PD‑L1 immunotherapy. We evaluated PD‑L1 expression in 4 breast cancer cell lines in the presence of 3 types of inhibitors, as well as IFN‑γ. The expression of phosphorylated signal transducer and activator of transcription 1 (p‑STAT1), one of the IFN‑γ signaling pathway molecules, was analyzed using immunohistochemistry (IHC) in relation to PD‑L1 and human leukocyte antigen (HLA) class I expression on cancer cells and tumor‑infiltrating CD8‑positive T cells in 111 patients with stage II/III breast cancer. Using The Cancer Genome Atlas (TCGA) database, the correlation of the IFN‑γ signature with PD‑L1 expression was analyzed in breast invasive carcinoma tissues. As a result, the JAK/STAT pathway via IFN‑γ was mainly involved in PD‑L1 expression in the cell lines examined. IHC analysis revealed that the PD‑L1 and HLA class I expression levels were significantly upregulated in the p‑STAT1‑positive cases. TCGA analysis indicated that the PD‑L1 expression and IFN‑γ signature exhibited a positive correlation. On the whole, these findings suggest that PD‑L1 and HLA class I are co‑expressed in p‑STAT1‑positive breast cancer cells induced by IFN‑γ secreted from tumor infiltrating immune cells, and that p‑STAT1 expression may be a potential biomarker for patient selection for immunotherapy with anti‑PD‑1/anti‑PD‑L1 monoclonal antibodies.

References

1 

Siegel RL, Miller KD and Jemal A: Cancer statistics, 2018. CA Cancer J Clin. 68:7–30. 2018. View Article : Google Scholar : PubMed/NCBI

2 

Wang J, Lv H, Xue Z, Wang L and Bai Z: Temporal Trends of Common Female Malignances on Breast, Cervical, and Ovarian Cancer Mortality in Japan, Republic of Korea, and Singapore: Application of the Age-Period-Cohort Model. BioMed Res Int. 2018:53074592018.PubMed/NCBI

3 

Sørlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, van de Rijn M, Jeffrey SS, et al: Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA. 98:10869–10874. 2001. View Article : Google Scholar : PubMed/NCBI

4 

Coates AS, Winer EP, Goldhirsch A, Gelber RD, Gnant M, Piccart-Gebhart M, Thürlimann B and Senn HJ; Panel Members: Tailoring therapies - improving the management of early breast cancer: St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2015. Ann Oncol. 26:1533–1546. 2015. View Article : Google Scholar : PubMed/NCBI

5 

Topalian SL, Drake CG and Pardoll DM: Immune checkpoint blockade: A common denominator approach to cancer therapy. Cancer Cell. 27:450–461. 2015. View Article : Google Scholar : PubMed/NCBI

6 

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

7 

Kang YK, Boku N, Satoh T, Ryu MH, Chao Y, Kato K, Chung HC, Chen JS, Muro K, Kang WK, et al: Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12 ATTRACTION-2): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 390:2461–2471. 2017. View Article : Google Scholar : PubMed/NCBI

8 

Escudier B, Motzer RJ, Sharma P, Wagstaff J, Plimack ER, Hammers HJ, Donskov F, Gurney H, Sosman JA, Zalewski PG, et al: Treatment Beyond Progression in Patients with Advanced Renal Cell Carcinoma Treated with Nivolumab in CheckMate 025. Eur Urol. 72:368–376. 2017. View Article : Google Scholar : PubMed/NCBI

9 

Nanda R, Chow LQ, Dees EC, Berger R, Gupta S, Geva R, Pusztai L, Pathiraja K, Aktan G, Cheng JD, et al: Pembrolizumab in Patients With Advanced Triple-Negative Breast Cancer: Phase Ib KEYNOTE-012 Study. J Clin Oncol. 34:2460–2467. 2016. View Article : Google Scholar : PubMed/NCBI

10 

Emens LA, Braiteh FS, Cassier P, Delord JP, Eder JP, Fasso M, Xiao Y, Wang Y, Molinero L, Chen DS, et al: Abstract 2859: Inhibition of PD-L1 by MPDL3280A leads to clinical activity in patients with metastatic triple-negative breast cancer (TNBC). Cancer Res. 75(Suppl 15): 28592015. View Article : Google Scholar

11 

Schmid P, Cruz C, Braiteh FS, Eder JP, Tolaney S, Kuter I, Nanda R, Chung C, Cassier P, Delord JP, et al: Abstract 2986: Atezolizumab in metastatic TNBC (mTNBC): Long-term clinical outcomes and biomarker analyses. Cancer Res. 77(Suppl 13): 29862017. View Article : Google Scholar

12 

Mizukami Y, Kono K, Maruyama T, Watanabe M, Kawaguchi Y, Kamimura K and Fujii H: Downregulation of HLA Class I molecules in the tumour is associated with a poor prognosis in patients with oesophageal squamous cell carcinoma. Br J Cancer. 99:1462–1467. 2008. View Article : Google Scholar : PubMed/NCBI

13 

Mimura K, Shiraishi K, Mueller A, Izawa S, Kua LF, So J, Yong WP, Fujii H, Seliger B, Kiessling R and Kono K: The MAPK pathway is a predominant regulator of HLA-A expression in esophageal and gastric cancer. J Immunol. 191:6261–6272. 2013. View Article : Google Scholar : PubMed/NCBI

14 

Mimura K, Teh JL, Okayama H, Shiraishi K, Kua LF, Koh V, Smoot DT, Ashktorab H, Oike T, Suzuki Y, et al: PD-L1 expression is mainly regulated by interferon gamma associated with JAK-STAT pathway in gastric cancer. Cancer Sci. 109:43–53. 2018. View Article : Google Scholar

15 

Schumacher TN and Schreiber RD: Neoantigens in cancer immunotherapy. Science. 348:69–74. 2015. View Article : Google Scholar : PubMed/NCBI

16 

Sobin LH, Gospodarowicz MK and Wittekind C: International Union against Cancer. TNM Classification of Malignant Tumours Wiley-Blackwell; West Sussex, UK; Hoboken, NJ: 2010

17 

Japanese Breast Cancer Society: General Rules for Clinical and Pathological Recording of Breast Cancer. 17th edition. Kanehara & Co. Ltd.; Tokyo: 2012

18 

Mimura K, Kua LF, Shiraishi K, Kee Siang L, Shabbir A, Komachi M, Suzuki Y, Nakano T, Yong WP, So J, et al: Inhibition of mitogen-activated protein kinase pathway can induce upregulation of human leukocyte antigen class I without PD-L1-upregulation in contrast to interferon-γ treatment. Cancer Sci. 105:1236–1244. 2014. View Article : Google Scholar : PubMed/NCBI

19 

Ayers M, Lunceford J, Nebozhyn M, Murphy E, Loboda A, Kaufman DR, Albright A, Cheng JD, Kang SP, Shankaran V, et al: IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade. J Clin Invest. 127:2930–2940. 2017. View Article : Google Scholar : PubMed/NCBI

20 

Wallin JJ, Bendell JC, Funke R, Sznol M, Korski K, Jones S, Hernandez G, Mier J, He X, Hodi FS, et al: Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma. Nat Commun. 7:126242016. View Article : Google Scholar : PubMed/NCBI

21 

Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, Sun Y, Jacobsen A, Sinha R, Larsson E, et al: Integrative analysis of complex cancer genomics and clinical profiles using the cBio-Portal. Sci Signal. 6:pl12013. View Article : Google Scholar

22 

Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, Jacobsen A, Byrne CJ, Heuer ML, Larsson E, et al: The cBio cancer genomics portal: An open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2:401–404. 2012. View Article : Google Scholar : PubMed/NCBI

23 

Sun D and Ding A: MyD88-mediated stabilization of interferon-gamma-induced cytokine and chemokine mRNA. Nat Immunol. 7:375–381. 2006. View Article : Google Scholar : PubMed/NCBI

24 

Liu J, Hamrouni A, Wolowiec D, Coiteux V, Kuliczkowski K, Hetuin D, Saudemont A and Quesnel B: Plasma cells from multiple myeloma patients express B7-H1 (PD-L1) and increase expression after stimulation with IFN-{gamma} and TLR ligands via a MyD88-, TRAF6-, and MEK-dependent pathway. Blood. 110:296–304. 2007. View Article : Google Scholar : PubMed/NCBI

25 

Yamamoto R, Nishikori M, Tashima M, Sakai T, Ichinohe T, Takaori-Kondo A, Ohmori K and Uchiyama T: B7-H1 expression is regulated by MEK/ERK signaling pathway in anaplastic large cell lymphoma and Hodgkin lymphoma. Cancer Sci. 100:2093–2100. 2009. View Article : Google Scholar : PubMed/NCBI

26 

Townsend A and Bodmer H: Antigen recognition by class I-restricted T lymphocytes. Annu Rev Immunol. 7:601–624. 1989. View Article : Google Scholar : PubMed/NCBI

27 

Šmahel M: PD-1/PD-L1 Blockade Therapy for Tumors with Downregulated MHC Class I Expression. Int J Mol Sci. 18:182017. View Article : Google Scholar

28 

Mittendorf EA, Philips AV, Meric-Bernstam F, Qiao N, Wu Y, Harrington S, Su X, Wang Y, Gonzalez-Angulo AM, Akcakanat A, et al: PD-L1 expression in triple-negative breast cancer. Cancer Immunol Res. 2:361–370. 2014. View Article : Google Scholar : PubMed/NCBI

29 

Fourcade J, Sun Z, Benallaoua M, Guillaume P, Luescher IF, Sander C, Kirkwood JM, Kuchroo V and Zarour HM: Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients. J Exp Med. 207:2175–2186. 2010. View Article : Google Scholar : PubMed/NCBI

30 

Liu B, Arakawa Y, Yokogawa R, Tokunaga S, Terada Y, Murata D, Matsui Y, Fujimoto KI, Fukui N, Tanji M, et al: PD-1/PD-L1 expression in a series of intracranial germinoma and its association with Foxp3+ and CD8+ infiltrating lymphocytes. PLoS One. 13:e01945942018. View Article : Google Scholar : PubMed/NCBI

31 

Huang AC, Postow MA, Orlowski RJ, Mick R, Bengsch B, Manne S, Xu W, Harmon S, Giles JR, Wenz B, et al: T-cell invigoration to tumour burden ratio associated with anti-PD-1 response. Nature. 545:60–65. 2017. View Article : Google Scholar : PubMed/NCBI

32 

Wang ZQ, Milne K, Derocher H, Webb JR, Nelson BH and Watson PH: PD-L1 and intratumoral immune response in breast cancer. Oncotarget. 8:51641–51651. 2017.PubMed/NCBI

33 

Muenst S, Schaerli AR, Gao F, Däster S, Trella E, Droeser RA, Muraro MG, Zajac P, Zanetti R, Gillanders WE, et al: Expression of programmed death ligand 1 (PD-L1) is associated with poor prognosis in human breast cancer. Breast Cancer Res Treat. 146:15–24. 2014. View Article : Google Scholar : PubMed/NCBI

34 

Mori H, Kubo M, Yamaguchi R, Nishimura R, Osako T, Arima N, Okumura Y, Okido M, Yamada M, Kai M, et al: The combination of PD-L1 expression and decreased tumor-infiltrating lymphocytes is associated with a poor prognosis in triple-negative breast cancer. Oncotarget. 8:15584–15592. 2017. View Article : Google Scholar : PubMed/NCBI

35 

Yagi T, Baba Y, Ishimoto T, Iwatsuki M, Miyamoto Y, Yoshida N, Watanabe M and Baba H: PD-L1 Expression, Tumor-infiltrating Lymphocytes, and Clinical Outcome in Patients With Surgically Resected Esophageal Cancer. Ann Surg. 269:471–478. 2019. View Article : Google Scholar

36 

Kawazoe A, Kuwata T, Kuboki Y, Shitara K, Nagatsuma AK, Aizawa M, Yoshino T, Doi T, Ohtsu A and Ochiai A: Clinicopathological features of programmed death ligand 1 expression with tumor-infiltrating lymphocyte, mismatch repair, and Epstein-Barr virus status in a large cohort of gastric cancer patients. Gastric Cancer. 20:407–415. 2017. View Article : Google Scholar

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June 2019
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Copy and paste a formatted citation
APA
Nakayama, Y., Mimura, K., Tamaki, T., Shiraishi, K., Kua, L., Koh, V. ... Kono, K. (2019). Phospho‑STAT1 expression as a potential biomarker for anti‑PD‑1/anti‑PD‑L1 immunotherapy for breast cancer. International Journal of Oncology, 54, 2030-2038. https://doi.org/10.3892/ijo.2019.4779
MLA
Nakayama, Y., Mimura, K., Tamaki, T., Shiraishi, K., Kua, L., Koh, V., Ohmori, M., Kimura, A., Inoue, S., Okayama, H., Suzuki, Y., Nakazawa, T., Ichikawa, D., Kono, K."Phospho‑STAT1 expression as a potential biomarker for anti‑PD‑1/anti‑PD‑L1 immunotherapy for breast cancer". International Journal of Oncology 54.6 (2019): 2030-2038.
Chicago
Nakayama, Y., Mimura, K., Tamaki, T., Shiraishi, K., Kua, L., Koh, V., Ohmori, M., Kimura, A., Inoue, S., Okayama, H., Suzuki, Y., Nakazawa, T., Ichikawa, D., Kono, K."Phospho‑STAT1 expression as a potential biomarker for anti‑PD‑1/anti‑PD‑L1 immunotherapy for breast cancer". International Journal of Oncology 54, no. 6 (2019): 2030-2038. https://doi.org/10.3892/ijo.2019.4779