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

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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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Abbreviations

CRC:

Colorectal cancer

DAMPs:

Danger-associated molecular patterns

DFS:

Disease-free survival

ICB:

Immune checkpoint blockade

ICD:

Immunogenic cell death

IFN-γ:

Interferon-γ

LARC:

Locally advanced rectal cancer

MSI:

Microsatellite instability

neoCRT:

Neoadjuvant chemoradiotherapy

OS:

Overall survival

pCR:

Pathologic complete response

PD-1:

Programmed cell death 1 receptor

PD-L1:

Programmed cell death 1 ligand 1

pN stage:

Pathologic lymph node stage

TILs:

Tumor-infiltrating lymphocytes

TMA:

Tissue microarray

TRG:

Tumor regression grade

References

  1. 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

    Article  PubMed  Google Scholar 

  2. 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

  3. 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

    Article  CAS  PubMed  Google Scholar 

  4. 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

    Article  PubMed  Google Scholar 

  5. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. 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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):1089–1096

    CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed  PubMed Central  Google Scholar 

  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)

    Article  Google Scholar 

  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)

    Article  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):9351–9359

    CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

This study was supported by grants from China Medical University Hospital [DMR-107-103 (Taiwan) and DMR-CELL-17022 (Taiwan)], Ministry of Science and Technology (MOST 107-2314-B-039 -027 -MY3, Taiwan), Ministry of Health, and Welfare (MOHW107-TDU-B-212-123004, Taiwan), and Health and welfare surcharge of tobacco products, China Medical University Hospital Cancer Research Center of Excellence (MOHW107-TDU-B-212-114024, Taiwan).

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Author notes

  1. William Tzu-Liang Chen and K. S. Clifford Chao contributed equally to this work.

Authors and Affiliations

  1. Cancer Center, China Medical University Hospital, China Medical University, 9F, Rehab Building, No. 2 Rude Rd, Taichung, 40402, Taiwan

    Shu-Fen Chiang, Ying-Shu You & K. S. Clifford Chao

  2. Translation Research Core, Medical University Hospital, China Medical University, Taichung, 40402, Taiwan

    Chih-Yang Huang

  3. Department of nutrition, HungKuang University, Taichung, 43302, Taiwan

    Chih-Yang Huang

  4. Department of Colorectal Surgery, China Medical University Hospital, China Medical University, 7F First Medical Building, No. 2 Rude Rd, Taichung, 40402, Taiwan

    Tao-Wei Ke & William Tzu-Liang Chen

  5. Department of Pathology, China Medical University Hospital, China Medical University, Taichung, 40402, Taiwan

    Tsung-Wei Chen

  6. Graduate Institute of Biomedical Science, China Medical University, Taichung, 40402, Taiwan

    Tsung-Wei Chen

  7. Department of Health Risk Management, China Medical University, Taichung, 40402, Taiwan

    Yu-Ching Lan

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  1. Shu-Fen Chiang
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Contributions

C-YH and S-FC conducted and performed the experiments; WT-LC, T-WK and T-WC enrolled the LARC patients and performed IHC evaluation; Y-SY and Y-CL performed the statistical analysis; S-FC and KSCC supervised this study; C-YH, S-FC, and KSCC analyzed the data and wrote the manuscript. All authors read and approved the final manuscript version.

Corresponding authors

Correspondence to William Tzu-Liang Chen or K. S. Clifford Chao.

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Chiang, SF., Huang, CY., Ke, TW. et al. Upregulation of tumor PD-L1 by neoadjuvant chemoradiotherapy (neoCRT) confers improved survival in patients with lymph node metastasis of locally advanced rectal cancers. Cancer Immunol Immunother 68, 283–296 (2019). https://doi.org/10.1007/s00262-018-2275-0

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