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The expression profile of PD-L1 and CD8+ lymphocyte in pituitary adenomas indicating for immunotherapy

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Abstract

Background

Pituitary adenomas (PAs) are the second most common brain tumors, and mostly are benign tumors. However, there exists subtypes of PAs refractory to common treatments, and need novel therapy. Programmed death 1 (PD-1) blockade has shown durable objective response in a variety of malignancies, and the key predictive markers for this immunotherapy were PD-L1 and CD8+ tumor-infiltrating lymphocyte (TILs) expression. To evaluate the potential immunotherapy for PAs, we investigated the expression of these two immune markers in PAs.

Methods

Immunohistochemistry (IHC) was performed to detect the expression of PD-L1 and CD8+ TILs in PAs. The ratio of positive expression of PD-L1 and CD8+ TILs was compared with chi-squared tests among different subtypes of PAs. The association between their expression profile and clinical parameters was analyzed using a chi-squared test, or Fisher’s exact probability test when appropriate.

Results

One hundred and ninety one patients with PAs were retrospectively involved in this study, consisting of 106 non-functioning PAs (NF-PAs, 55.5%), 40 PRL-secreting PAs (PRL-PAs, 20.9%), 31 GH-secreting PAs (GH-PAs, 16.2%), 9 ACTH-secreting PAs (ACTH-PAs, 4.7%) and 5 plurihormonal adenomas (2.6%) respectively. 36.6% of them were PD-L1 positive and 86.9% were CD8+ TILs positive. The positive PD-L1 immunostaining presented more frequently in functioning PAs (58.8%), compared with that (34.3%) in nonfunctioning group (p = 0.000). Moreover, the rates of PD-L1 expression were more associated with increased blood levels of PRL, GH, ACTH and cortisol. Contrastly, positive CD8+ TILs immunostaining was only correlated with elevated blood level of GH. For the analysis of immune markers with pathological results, PD-L1 expression was associated with PRL and GH immunostaining and higher Ki-67 index. But CD8+ TILs was only correlated with PRL immunostaining.

Conclusion

Our results showed that PD-L1 was frequently expressed in functioning PAs with association of aggressive behaviors in PAs. The immunotherapy could be a promising treatment option of PAs.

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References

  1. Ostrom QT, Gittleman H, Xu J, Kromer C, Wolinsky Y, Kruchko C, Barnholtz-Sloan JS (2016) CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2009–2013. Neuro Oncol 18(suppl_5):v1–v75. https://doi.org/10.1093/neuonc/now207

    Article  PubMed  Google Scholar 

  2. Aflorei ED, Korbonits M (2014) Epidemiology and etiopathogenesis of pituitary adenomas. J Neuro 117(3):379–394

    Google Scholar 

  3. Song ZJ, Reitman ZJ, Ma ZY, Chen JH, Zhang QL, Shou XF, Huang CX, Wang YF, Li SQ, Mao Y, Zhou LF, Lian BF, Yan H, Shi YY, Zhao Y (2016) The genome-wide mutational landscape of pituitary adenomas. Cell Res. https://doi.org/10.1038/cr.2016.114

    Article  PubMed  PubMed Central  Google Scholar 

  4. Molitch ME (2017) Diagnosis and treatment of pituitary adenomas: a review. JAMA 317(5):516–524. https://doi.org/10.1001/jama.2016.19699

    Article  PubMed  Google Scholar 

  5. Di Ieva A, Rotondo F, Syro LV, Cusimano MD, Kovacs K (2014) Aggressive pituitary adenomas–diagnosis and emerging treatments. Nat Rev Endocrinol 10(7):423–435. https://doi.org/10.1038/nrendo.2014.64

    Article  PubMed  CAS  Google Scholar 

  6. Lopes MBS (2017) The 2017 World Health Organization classification of tumors of the pituitary gland: a summary. Acta Neuropathol. https://doi.org/10.1007/s00401-017-1769-8

    Article  PubMed  Google Scholar 

  7. Mellman I, Coukos G, Dranoff G (2011) Cancer immunotherapy comes of age. Nat Clin Pract Oncol 2(3):480–489

    Google Scholar 

  8. Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O’Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR, Investigators K- (2016) Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 375(19):1823–1833. https://doi.org/10.1056/NEJMoa1606774

    Article  PubMed  CAS  Google Scholar 

  9. Weber JS, D’Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, Hoeller C, Khushalani NI, Miller WH Jr, Lao CD, Linette GP, Thomas L, Lorigan P, Grossmann KF, Hassel JC, Maio M, Sznol M, Ascierto PA, Mohr P, Chmielowski B, Bryce A, Svane IM, Grob JJ, Krackhardt AM, Horak C, Lambert A, Yang AS, Larkin J (2015) Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol 16(4):375–384. https://doi.org/10.1016/S1470-2045(15)70076-8

    Article  PubMed  CAS  Google Scholar 

  10. Mei Y, Bi WL, Greenwald NF, Du Z, Agar NY, Kaiser UB, Woodmansee WW, Reardon DA, Freeman GJ, Fecci PE, Laws ER Jr, Santagata S, Dunn GP, Dunn IF (2016) Increased expression of programmed death ligand 1 (PD-L1) in human pituitary tumors. Oncotarget 7(47):76565–76576. https://doi.org/10.18632/oncotarget.12088

    Article  PubMed  PubMed Central  Google Scholar 

  11. Rizvi NA, Mazieres J, Planchard D, Stinchcombe TE, Dy GK, Antonia SJ, Horn L, Lena H, Minenza E, Mennecier B, Otterson GA, Campos LT, Gandara DR, Levy BP, Nair SG, Zalcman G, Wolf J, Souquet PJ, Baldini E, Cappuzzo F, Chouaid C, Dowlati A, Sanborn R, Lopez-Chavez A, Grohe C, Huber RM, Harbison CT, Baudelet C, Lestini BJ, Ramalingam SS (2015) Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol 16(3):257–265. https://doi.org/10.1016/S1470-2045(15)70054-9

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. D’Angelo SP, Shoushtari AN, Agaram NP, Kuk D, Qin LX, Carvajal RD, Dickson MA, Gounder M, Keohan ML, Schwartz GK, Tap WD (2015) Prevalence of tumor-infiltrating lymphocytes and PD-L1 expression in the soft tissue sarcoma microenvironment. Hum Pathol 46(3):357–365. https://doi.org/10.1016/j.humpath.2014.11.001

    Article  PubMed  CAS  Google Scholar 

  13. Dai C, Sun B, Liu X, Bao X, Feng M, Yao Y, Wei J, Deng K, Yang C, Li X, Ma W, Wang R (2017) O-6-Methylguanine-DNA methyltransferase expression is associated with pituitary adenoma tumor recurrence: a systematic meta-analysis. Oncotarget 8(12):19674–19683. https://doi.org/10.18632/oncotarget.14936

    Article  PubMed  PubMed Central  Google Scholar 

  14. Sun Z, Fourcade J, Pagliano O, Chauvin J-M, Sander C, Kirkwood JM, Zarour HM (2015) IL10 and PD-1 cooperate to limit the activity of tumor-specific CD8+ T cells. Cancer Res 75(8):1635–1644

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Parsa AT, Waldron JS, Panner A, Crane CA, Parney IF, Barry JJ, Cachola KE, Murray JC, Tihan T, Jensen MC (2007) Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nat Med 13(1):84

    Article  PubMed  CAS  Google Scholar 

  16. Ota K, Azuma K, Kawahara A, Hattori S, Iwama E, Tanizaki J, Harada T, Matsumoto K, Takayama K, Takamori S (2015) Induction of PD-L1 expression by the EML4–ALK oncoprotein and downstream signaling pathways in non–small cell lung cancer. Clin Cancer Res 21(17):4014–4021

    Article  PubMed  CAS  Google Scholar 

  17. Lastwika KJ, Wilson W, Li QK, Norris J, Xu H, Ghazarian SR, Kitagawa H, Kawabata S, Taube JM, Yao S (2016) Control of PD-L1 expression by oncogenic activation of the AKT-mTOR pathway in non-small cell lung cancer. Cancer Res 76(2):227–238

    Article  PubMed  CAS  Google Scholar 

  18. Marzec M, Zhang Q, Goradia A, Raghunath PN, Liu X, Paessler M, Wang HY, Wysocka M, Cheng M, Ruggeri BA (2008) Oncogenic kinase NPM/ALK induces through STAT3 expression of immunosuppressive protein CD274 (PD-L1, B7-H1). Proc Natl Acad Sci USA 105(52):20852–20857

    Article  PubMed  Google Scholar 

  19. Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12(4):252

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Jiang X, Zhou J, Giobbie-Hurder A, Wargo J, Hodi FS (2013) The activation of MAPK in melanoma cells resistant to BRAF inhibition promotes PD-L1 expression that is reversible by MEK and PI3K inhibition. Clin Cancer Res 19(3):598–609

    Article  PubMed  CAS  Google Scholar 

  21. Abiko K, Matsumura N, Hamanishi J, Horikawa N, Murakami R, Yamaguchi K, Yoshioka Y, Baba T, Konishi I, Mandai M (2015) IFN-γ from lymphocytes induces PD-L1 expression and promotes progression of ovarian cancer. Br J Cancer 112(9):1501

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Ni L, Dong C (2017) New checkpoints in cancer immunotherapy. Immunol Rev 276(1):52–65. https://doi.org/10.1111/imr.12524

    Article  PubMed  CAS  Google Scholar 

  23. Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12(4):252–264. https://doi.org/10.1038/nrc3239

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Teng MW, Ngiow SF, Ribas A, Smyth MJ (2015) Classifying cancers based on T-cell infiltration and PD-L1. Cancer Res 75(11):2139–2145. https://doi.org/10.1158/0008-5472.CAN-15-0255

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Mei Y, Bi WL, Greenwald NF, Du Z, Agar NY, Kaiser UB, Woodmansee WW, Reardon DA, Freeman GJ, Fecci PE, Laws ER Jr, Santagata S, Dunn GP, Dunn IF (2016) Increased expression of programmed death ligand 1 (PD-L1) in human pituitary tumors. Oncotarget. https://doi.org/10.18632/oncotarget.12088

    Article  PubMed  PubMed Central  Google Scholar 

  26. Lupi I, Manetti L, Caturegli P, Menicagli M, Cosottini M, Iannelli A, Acerbi G, Bevilacqua G, Bogazzi F, Martino E (2010) Tumor infiltrating lymphocytes but not serum pituitary antibodies are associated with poor clinical outcome after surgery in patients with pituitary adenoma. J Clin Endocrinol Metab 95(1):289–296. https://doi.org/10.1210/jc.2009-1583

    Article  PubMed  CAS  Google Scholar 

  27. Lu JQ, Adam B, Jack AS, Lam A, Broad RW, Chik CL (2015) Immune cell infiltrates in pituitary adenomas: more macrophages in larger adenomas and more T cells in growth hormone adenomas. Endocr Pathol 26(3):263–272. https://doi.org/10.1007/s12022-015-9383-6

    Article  PubMed  CAS  Google Scholar 

  28. Richardson TE, Shen ZJ, Kanchwala M, Xing C, Filatenkov A, Shang P, Barnett S, Abedin Z, Malter JS, Raisanen JM, Burns DK, White CL, Hatanpaa KJ (2017) Aggressive behavior in silent subtype III pituitary adenomas may depend on suppression of local immune response: a whole transcriptome analysis. J Neuropathol Exp Neurol 76(10):874–882. https://doi.org/10.1093/jnen/nlx072

    Article  PubMed  Google Scholar 

  29. Deng L, Liang H, Burnette B, Beckett M, Darga T, Weichselbaum RR, Fu YX (2014) Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Investig 124(2):687–695. https://doi.org/10.1172/JCI67313

    Article  PubMed  CAS  Google Scholar 

  30. Mathios D, Kim JE, Mangraviti A, Phallen J, Park CK, Jackson CM, Garzon-Muvdi T, Kim E, Theodros D, Polanczyk M, Martin AM, Suk I, Ye X, Tyler B, Bettegowda C, Brem H, Pardoll DM, Lim M (2016) Anti-PD-1 antitumor immunity is enhanced by local and abrogated by systemic chemotherapy in GBM. Sci Transl Med 8(370):370ra180. https://doi.org/10.1126/scitranslmed.aag2942

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Wolchok JD, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, Lao CD, Wagstaff J, Schadendorf D, Ferrucci PF, Smylie M, Dummer R, Hill A, Hogg D, Haanen J, Carlino MS, Bechter O, Maio M, Marquez-Rodas I, Guidoboni M, McArthur G, Lebbe C, Ascierto PA, Long GV, Cebon J, Sosman J, Postow MA, Callahan MK, Walker D, Rollin L, Bhore R, Hodi FS, Larkin J (2017) Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. https://doi.org/10.1056/NEJMoa1709684

    Article  PubMed Central  PubMed  Google Scholar 

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Acknowledgements

This work was supported by grants from National Key Technology Research and Development Program of the Ministry of Science and Technology of China (No.2014BAI04B01) and The National Brain Tumor Registry of China (2015BAI12B04).

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  1. Peng-fei Wang and Ting-jian Wang equally contributed to this work.

Authors and Affiliations

  1. Department of Neurosurgery, Sanbo Brain Hospital, Capital Medical University, Beijing, China

    Peng-fei Wang, Ting-jian Wang, Ya-kun Yang & Chang-Xiang Yan

  2. Department of Pathology, Sanbo Brain Hospital, Capital Medical University, Beijing, China

    Kun Yao

  3. Institute of Laboratory Animal Sciences, Comparative Medicine Center, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China

    Zhuo Li

  4. Department of Neurosurgery and Oncology, University of Rochester Medical Center, 601 Elmwood Ave, Rm 2.8121, Box 670, Rochester, NY, 14642, USA

    Yan Michael Li

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Wang, Pf., Wang, Tj., Yang, Yk. et al. The expression profile of PD-L1 and CD8+ lymphocyte in pituitary adenomas indicating for immunotherapy. J Neurooncol 139, 89–95 (2018). https://doi.org/10.1007/s11060-018-2844-2

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