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01-02-2019 | Original Article

Upregulation of tumor PD-L1 by neoadjuvant chemoradiotherapy (neoCRT) confers improved survival in patients with lymph node metastasis of locally advanced rectal cancers

Authors: Shu-Fen Chiang, Chih-Yang Huang, Tao-Wei Ke, Tsung-Wei Chen, Yu-Ching Lan, Ying-Shu You, William Tzu-Liang Chen, K. S. Clifford Chao

Published in: Cancer Immunology, Immunotherapy | Issue 2/2019

Abstract

The expression of programmed cell death 1 ligand 1 (PD-L1) and interferon-γ (IFN-γ) is of great interest for the development of chemoradiotherapy and immune checkpoint inhibitor treatments. Patients with nodal metastasis (pN+) tend to have a poor prognosis, even after neoadjuvant chemoradiotherapy (neoCRT) and surgical treatment. In this study, we examined the roles of tumor PD-L1 and IFN-γ before and after neoCRT in locally advanced rectal cancer (LARC) patients. Our results demonstrate that patients with high PD-L1 expression in post-neoCRT tissues exhibit improved 5-year disease-free survival (DFS) and overall survival (OS) compared with those with low PD-L1 expression (p < 0.001). Furthermore, in the pN+ population, patients with high PD-L1 expression in post-neoCRT tissues exhibit improved 5-year DFS and OS. PD-L1 and IFN-γ upregulation increased in tumor tissues after neoCRT, and patients with high PD-L1 and high IFN-γ exhibit improved 5-year DFS and OS (p = 0.04 and p = 0.001, respectively). To the best of our knowledge, this study is the first to demonstrate that PD-L1 upregulation in a pN+ cohort correlates with improved prognosis, which is similar to that in patients without nodal metastasis. Moreover, this study verified that PD-L1 and IFN-γ were upregulated by neoCRT treatment in LARC patients and demonstrated that neoCRT may be useful not only for immune checkpoint inhibitor treatment but also for reinvigorating preexisting anti-cancer immunity.

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Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ (2009) Cancer statistics, 2009. CA Cancer J Clin 59(4):225–249. https://doi.org/10.3322/caac.20006 CrossRefPubMed

Conde-Muino R, Cuadros M, Zambudio N, Segura-Jimenez I, Cano C, Palma P (2015) Predictive biomarkers to chemoradiation in locally advanced rectal cancer. Biomed Res Int 2015:921435. https://doi.org/10.1155/2015/921435

Sauer R, Liersch T, Merkel S, Fietkau R, Hohenberger W, Hess C, Becker H, Raab HR, Villanueva MT, Witzigmann H, Wittekind C, Beissbarth T, Rodel C (2012) Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: results of the German CAO/ARO/AIO-94 randomized phase III trial after a median follow-up of 11 years. J Clin Oncol 30(16):1926–1933. https://doi.org/10.1200/JCO.2011.40.1836 CrossRefPubMed

Yoon WH, Kim HJ, Kim CH, Joo JK, Kim YJ, Kim HR (2015) Oncologic impact of pathologic response on clinical outcome after preoperative chemoradiotherapy in locally advanced rectal cancer. Ann Surg Treat Res 88(1):15–20. https://doi.org/10.4174/astr.2015.88.1.15 CrossRefPubMed

Balko JM, Black EP (2009) A gene expression predictor of response to EGFR-targeted therapy stratifies progression-free survival to cetuximab in KRAS wild-type metastatic colorectal cancer. BMC Cancer 9:145. https://doi.org/10.1186/1471-2407-9-145 CrossRefPubMedPubMedCentral

Wennerberg E, Vanpouille-Box C, Bornstein S, Yamazaki T, Demaria S, Galluzzi L (2017) Immune recognition of irradiated cancer cells. Immunol Rev 280(1):220–230. https://doi.org/10.1111/imr.12568 CrossRefPubMedPubMedCentral

Showalter A, Limaye A, Oyer JL, Igarashi R, Kittipatarin C, Copik AJ, Khaled AR (2017) Cytokines in immunogenic cell death: applications for cancer immunotherapy. Cytokine 97:123–132. https://doi.org/10.1016/j.cyto.2017.05.024 CrossRefPubMedPubMedCentral

Zaidi MR, Merlino G (2011) The two faces of interferon-gamma in cancer. Clin Cancer Res 17(19):6118–6124. https://doi.org/10.1158/1078-0432.CCR-11-0482 CrossRefPubMedPubMedCentral

Keir ME, Butte MJ, Freeman GJ, Sharpe AH (2008) PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 26:677–704. https://doi.org/10.1146/annurev.immunol.26.021607.090331 CrossRefPubMed

10.

Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wigginton JM, Sznol M (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366(26):2443–2454. https://doi.org/10.1056/NEJMoa1200690 CrossRefPubMedPubMedCentral

11.

Hirano F, Kaneko K, Tamura H, Dong H, Wang S, Ichikawa M, Rietz C, Flies DB, Lau JS, Zhu G, Tamada K, Chen L (2005) Blockade of B7-H1 and PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer Res 65(3):1089–1096PubMed

12.

Wang X, Teng F, Kong L, Yu J (2016) PD-L1 expression in human cancers and its association with clinical outcomes. Onco Targets Ther 9:5023–5039. https://doi.org/10.2147/OTT.S105862 CrossRefPubMedPubMedCentral

13.

Patel SP, Kurzrock R (2015) PD-L1 expression as a predictive biomarker in cancer immunotherapy. Mol Cancer Ther 14(4):847–856. https://doi.org/10.1158/1535-7163.MCT-14-0983 CrossRefPubMed

14.

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

15.

Ritprajak P, Azuma M (2015) Intrinsic and extrinsic control of expression of the immunoregulatory molecule PD-L1 in epithelial cells and squamous cell carcinoma. Oral Oncol 51(3):221–228. https://doi.org/10.1016/j.oraloncology.2014.11.014 CrossRefPubMed

16.

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 CrossRefPubMedPubMedCentral

17.

Dovedi SJ, Adlard AL, Lipowska-Bhalla G, McKenna C, Jones S, Cheadle EJ, Stratford IJ, Poon E, Morrow M, Stewart R, Jones H, Wilkinson RW, Honeychurch J, Illidge TM (2014) Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade. Cancer Res 74(19):5458–5468. https://doi.org/10.1158/0008-5472.CAN-14-1258 CrossRefPubMed

18.

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(200):200ra116. https://doi.org/10.1126/scitranslmed.3006504 CrossRefPubMedPubMedCentral

19.

Li Y, Liang L, Dai W, Cai G, Xu Y, Li X, Li Q, Cai S (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(1):55. https://doi.org/10.1186/s12943-016-0539-x CrossRefPubMedPubMedCentral

20.

Benci JL, Xu B, Qiu Y, Wu TJ, Dada H, Twyman-Saint Victor C, Cucolo L, Lee DSM, Pauken KE, Huang AC, Gangadhar TC, Amaravadi RK, Schuchter LM, Feldman MD, Ishwaran H, Vonderheide RH, Maity A, Wherry EJ, Minn AJ (2016) Tumor interferon signaling regulates a multigenic resistance program to immune checkpoint blockade. Cell 167(6):1540–1554 e1512. https://doi.org/10.1016/j.cell.2016.11.022 CrossRefPubMedPubMedCentral

21.

Droeser RA, Hirt C, Viehl CT, Frey DM, Nebiker C, Huber X, Zlobec I, Eppenberger-Castori S, Tzankov A, Rosso R, Zuber M, Muraro MG, Amicarella F, Cremonesi E, Heberer M, Iezzi G, Lugli A, Terracciano L, Sconocchia G, Oertli D, Spagnoli GC, Tornillo L (2013) Clinical impact of programmed cell death ligand 1 expression in colorectal cancer. Eur J Cancer 49(9):2233–2242. https://doi.org/10.1016/j.ejca.2013.02.015 CrossRefPubMed

22.

Huang CY, Chiang SF, Ke TW, Chen TW, Lan YC, You YS, Shiau AC, Chen WT, Chao KSC (2018) 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. Cancer Immunol Immunother 67(4):551–562. https://doi.org/10.1007/s00262-017-2109-5 CrossRefPubMed

23.

Thompson RH, Kuntz SM, Leibovich BC, Dong H, Lohse CM, Webster WS, Sengupta S, Frank I, Parker AS, Zincke H, Blute ML, Sebo TJ, Cheville JC, Kwon ED (2006) Tumor B7-H1 is associated with poor prognosis in renal cell carcinoma patients with long-term follow-up. Cancer Res 66(7):3381–3385. https://doi.org/10.1158/0008-5472.CAN-05-4303 CrossRefPubMed

24.

Liu LC, Su CH, Wang HC, Chang WS, Tsai CW, Maa MC, Tsai CH, Tsai FJ, Bau DT (2014) Contribution of personalized Cyclin D1 genotype to triple negative breast cancer risk. BioMedicine 4 (1). https://doi.org/10.7603/s40681-014-0003-4

25.

Wang X, Sheu JJC, Lai MT, Yin-Yi Chang C, Sheng X, Wei L, Gao Y, Wang X, Liu N, Xie W, Chen C-M, Ding WY, Sun L (2018) RSF-1 overexpression determines cancer progression and drug resistance in cervical cancer. BioMedicine 8(1):4. https://doi.org/10.1051/bmdcn/2018080104 CrossRefPubMedPubMedCentral

26.

Chao KSC, Chen WTL, Ke TW, Chiang SF, Chen TW, Huang CY, You YS, Kuo YC (2016) Acquired immunity trumps ypN + and TRG as the sole prognostic biomarker for locally advanced rectal cancer (LARC) treated with neoadjuvant chemoradiation therapy (NeoCRT). ASTRO annual meeting 2016. Int J Radiat Oncol Biol Phys 96 (2): S100. https://doi.org/10.1016/j.ijrobp.2016.06.265 (suppl; abstract 242)CrossRef

27.

Huang CY, Chiang SF, Chen TLW, Ke TW, Chen TW, You YS, Chao KSC (2017) Upregulation of tumor PD-L1 by neoCRT may hold the key to successes in patients with pN + locally advanced rectal cancer. ASTRO annual meeting 2017. Int J Radiat Oncol Biol Phys 99 (2):S65. https://doi.org/10.1016/j.ijrobp.2017.06.160 (suppl; abstract 139)CrossRef

28.

Francisco LM, Sage PT, Sharpe AH (2010) The PD-1 pathway in tolerance and autoimmunity. Immunol Rev 236:219–242. https://doi.org/10.1111/j.1600-065X.2010.00923.x CrossRefPubMedPubMedCentral

29.

Hino R, Kabashima K, Kato Y, Yagi H, Nakamura M, Honjo T, Okazaki T, Tokura Y (2010) Tumor cell expression of programmed cell death-1 ligand 1 is a prognostic factor for malignant melanoma. Cancer 116(7):1757–1766. https://doi.org/10.1002/cncr.24899 CrossRefPubMed

30.

Mu CY, Huang JA, Chen Y, Chen C, Zhang XG (2011) High expression of PD-L1 in lung cancer may contribute to poor prognosis and tumor cells immune escape through suppressing tumor infiltrating dendritic cells maturation. Med Oncol 28(3):682–688. https://doi.org/10.1007/s12032-010-9515-2 CrossRefPubMed

31.

Shin SJ, Jeon YK, Kim PJ, Cho YM, Koh J, Chung DH, Go H (2016) Clinicopathologic analysis of PD-L1 and PD-L2 expression in renal cell carcinoma: association with oncogenic proteins status. Ann Surg Oncol 23(2):694–702. https://doi.org/10.1245/s10434-015-4903-7 CrossRefPubMed

32.

Wu P, Wu D, Li L, Chai Y, Huang J (2015) PD-L1 and survival in solid tumors: a meta-analysis. PLoS One 10(6):e0131403. https://doi.org/10.1371/journal.pone.0131403 CrossRefPubMedPubMedCentral

33.

Eto S, Yoshikawa K, Nishi M, Higashijima J, Tokunaga T, Nakao T, Kashihara H, Takasu C, Iwata T, Shimada M (2016) Programmed cell death protein 1 expression is an independent prognostic factor in gastric cancer after curative resection. Gastric Cancer 19(2):466–471. https://doi.org/10.1007/s10120-015-0519-7 CrossRefPubMed

34.

Muenst S, Schaerli AR, Gao F, Daster S, Trella E, Droeser RA, Muraro MG, Zajac P, Zanetti R, Gillanders WE, Weber WP, Soysal SD (2014) Expression of programmed death ligand 1 (PD-L1) is associated with poor prognosis in human breast cancer. Breast Cancer Res Treat 146(1):15–24. https://doi.org/10.1007/s10549-014-2988-5 CrossRefPubMedPubMedCentral

35.

Zhu H, Qin H, Huang Z, Li S, Zhu X, He J, Yang J, Yu X, Yi X (2015) Clinical significance of programmed death ligand-1 (PD-L1) in colorectal serrated adenocarcinoma. Int J Clin Exp Pathol 8(8):9351–9359PubMedPubMedCentral

36.

Koganemaru S, Inoshita N, Miura Y, Miyama Y, Fukui Y, Ozaki Y, Tomizawa K, Hanaoka Y, Toda S, Suyama K, Tanabe Y, Moriyama J, Fujii T, Matoba S, Kuroyanagi H, Takano T (2017) Prognostic value of programmed death-ligand 1 expression in patients with stage III colorectal cancer. Cancer Sci 108(5):853–858. https://doi.org/10.1111/cas.13229 CrossRefPubMedPubMedCentral

37.

Schalper KA, Velcheti V, Carvajal D, Wimberly H, Brown J, Pusztai L, Rimm DL (2014) In situ tumor PD-L1 mRNA expression is associated with increased TILs and better outcome in breast carcinomas. Clin Cancer Res 20(10):2773–2782. https://doi.org/10.1158/1078-0432.CCR-13-2702 CrossRefPubMed

38.

Sabatier R, Finetti P, Mamessier E, Adelaide J, Chaffanet M, Ali HR, Viens P, Caldas C, Birnbaum D, Bertucci F (2015) Prognostic and predictive value of PDL1 expression in breast cancer. Oncotarget 6(7):5449–5464. https://doi.org/10.18632/oncotarget.3216 CrossRefPubMed

39.

Baptista MZ, Sarian LO, Derchain SF, Pinto GA, Vassallo J (2016) Prognostic significance of PD-L1 and PD-L2 in breast cancer. Hum Pathol 47(1):78–84. https://doi.org/10.1016/j.humpath.2015.09.006 CrossRefPubMed

40.

Velcheti V, Schalper KA, Carvajal DE, Anagnostou VK, Syrigos KN, Sznol M, Herbst RS, Gettinger SN, Chen L, Rimm DL (2014) Programmed death ligand-1 expression in non-small cell lung cancer. Lab Investig 94(1):107–116. https://doi.org/10.1038/labinvest.2013.130 CrossRefPubMed

41.

Taube JM, Anders RA, Young GD, Xu H, Sharma R, McMiller TL, Chen S, Klein AP, Pardoll DM, Topalian SL, Chen L (2012) Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl Med 4(127):127ra137. https://doi.org/10.1126/scitranslmed.3003689 CrossRef

42.

Hecht M, Buttner-Herold M, Erlenbach-Wunsch K, Haderlein M, Croner R, Grutzmann R, Hartmann A, Fietkau R, Distel LV (2016) PD-L1 is upregulated by radiochemotherapy in rectal adenocarcinoma patients and associated with a favourable prognosis. Eur J Cancer 65:52–60. https://doi.org/10.1016/j.ejca.2016.06.015 CrossRefPubMed

43.

Zeng J, See AP, Phallen J, Jackson CM, Belcaid Z, Ruzevick J, Durham N, Meyer C, Harris TJ, Albesiano E, Pradilla G, Ford E, Wong J, Hammers HJ, Mathios D, Tyler B, Brem H, Tran PT, Pardoll D, Drake CG, Lim M (2013) Anti-PD-1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas. Int J Radiat Oncol Biol Phys 86(2):343–349. https://doi.org/10.1016/j.ijrobp.2012.12.025 CrossRefPubMedPubMedCentral

44.

Wu CT, Chen WC, Chang YH, Lin WY, Chen MF (2016) The role of PD-L1 in the radiation response and clinical outcome for bladder cancer. Sci Rep 6:19740. https://doi.org/10.1038/srep19740 CrossRefPubMedPubMedCentral

45.

Saigusa S, Toiyama Y, Tanaka K, Inoue Y, Mori K, Ide S, Imaoka H, Kawamura M, Mohri Y, Kusunoki M (2016) Implication of programmed cell death ligand 1 expression in tumor recurrence and prognosis in rectal cancer with neoadjuvant chemoradiotherapy. Int J Clin Oncol 21(5):946–952. https://doi.org/10.1007/s10147-016-0962-4 CrossRefPubMed

46.

Lim SH, Hong M, Ahn S, Choi YL, Kim KM, Oh D, Ahn YC, Jung SH, Ahn MJ, Park K, Zo JI, Shim YM, Sun JM (2016) Changes in tumour expression of programmed death-ligand 1 after neoadjuvant concurrent chemoradiotherapy in patients with squamous oesophageal cancer. Eur J Cancer 52:1–9. https://doi.org/10.1016/j.ejca.2015.09.019 CrossRefPubMed

47.

Jomrich G, Silberhumer GR, Marian B, Beer A, Mullauer L (2016) Programmed death-ligand 1 expression in rectal cancer. Eur Surg 48(6):352–356. https://doi.org/10.1007/s10353-016-0447-8 CrossRefPubMedPubMedCentral

Title: Upregulation of tumor PD-L1 by neoadjuvant chemoradiotherapy (neoCRT) confers improved survival in patients with lymph node metastasis of locally advanced rectal cancers
Authors: Shu-Fen Chiang
Chih-Yang Huang
Tao-Wei Ke
Tsung-Wei Chen
Yu-Ching Lan
Ying-Shu You
William Tzu-Liang Chen
K. S. Clifford Chao
Publication date: 01-02-2019
Publisher: Springer Berlin Heidelberg
Published in: Cancer Immunology, Immunotherapy / Issue 2/2019
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-018-2275-0

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