Top

Published in:

01-07-2017 | Original Article

Prognostic implication of CD274 (PD-L1) protein expression in tumor-infiltrating immune cells for microsatellite unstable and stable colorectal cancer

Authors: Kyu Sang Lee, Yoonjin Kwak, Soyeon Ahn, Eun Shin, Heung-Kwon Oh, Duck-Woo Kim, Sung-Bum Kang, Gheeyoung Choe, Woo Ho Kim, Hye Seung Lee

Published in: Cancer Immunology, Immunotherapy | Issue 7/2017

Abstract

In this study, we investigated the clinical relevance of CD274 (PD-L1) protein expression by tumor cells and tumor-infiltrating immune cells in colorectal cancer (CRC). To this end, 186 microsatellite instability-high (MSI-H) and 153 microsatellite stable (MSS) CRCs were subjected to immunohistochemistry (IHC) analysis for the expression of CD274 and mismatch repair proteins. CD274 expression was evaluated in tumor cells at the center (TC) and periphery (TP), and immune cells at the center (IC) and periphery (IP) of CRC. IHC slides stained for CD3 and CD8 were scanned using an Aperio ScanScope for precise calculation of tumor-infiltrating T cell density. Additionally, samples were screened for the B-Raf (BRAF)-V600E mutation using a Cobas 4800 System and IHC. In total, CD274^TC, CD274^TP, CD274^IC, and CD274^IP were observed in 43 (23.1%), 47 (25.3%), 107 (57.5%), and 102 (54.8%) of the MSI-H CRCs examined, and in three (2.0%), four (2.6%), 47 (30.7%), and 56 (36.6%) of the 153 MSS CRCs tested. Meanwhile, intratumoral heterogeneity of CD274 expression in tumor cells and immune cells was detected in 24 (12.9%) and 47 (25.3%) MSI-H CRCs, respectively. Notably, in both MSI-H and MSS CRC, CD274^IC and CD274^IP were independently associated with improved prognosis (P < 0.05), while BRAF mutation was associated with CD274^TP, poor differentiation, sporadic type, and hMLH1(−)/hMSH2(+)/hMSH6(+)/PMS2(−) in MSI-H CRC (P < 0.006). In conclusion, CD274 expression in tumor-infiltrating immune cells was an independent factor for improved prognosis in CRC patients. A deeper understanding of CD274 status may yield improved responses to future CRC immunotherapies.

Available only for authorised users

Sznol M, Chen L (2013) Antagonist antibodies to PD-1 and B7-H1 (PD-L1) in the treatment of advanced human cancer. Clin Cancer Res 19(5):1021–1034. doi:10.1158/1078-0432.CCR-12-2063 CrossRefPubMedPubMedCentral

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

Azuma T, Yao S, Zhu G, Flies AS, Flies SJ, Chen L (2008) B7-H1 is a ubiquitous antiapoptotic receptor on cancer cells. Blood 111(7):3635–3643. doi:10.1182/blood-2007-11-123141 CrossRefPubMedPubMedCentral

Herbst RS, Baas P, Kim DW, Felip E, Perez-Gracia JL, Han JY, Molina J, Kim JH, Arvis CD, Ahn MJ, Majem M, Fidler MJ, de Castro G Jr, Garrido M, Lubiniecki GM, Shentu Y, Im E, Dolled-Filhart M, Garon EB (2016) Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 387(10027):1540–1550. doi:10.1016/S0140-6736(15)01281-7 CrossRefPubMed

Rosenbaum MW, Bledsoe JR, Morales-Oyarvide V, Huynh TG, Mino-Kenudson M (2016) PD-L1 expression in colorectal cancer is associated with microsatellite instability, BRAF mutation, medullary morphology and cytotoxic tumor-infiltrating lymphocytes. Mod Pathol 29(9):1104–1112. doi:10.1038/modpathol.2016.95 CrossRefPubMed

Kim JH, Park HE, Cho NY, Lee HS, Kang GH (2016) Characterisation of PD-L1-positive subsets of microsatellite-unstable colorectal cancers. Br J Cancer 115(4):490–496. doi:10.1038/bjc.2016.211 CrossRefPubMed

Asaoka Y, Ijichi H, Koike K (2015) PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 373(20):1979. doi:10.1056/NEJMc1510353#SA1 CrossRefPubMed

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. doi:10.1371/journal.pone.0131403 CrossRefPubMedPubMedCentral

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. doi:10.1016/j.ejca.2013.02.015 CrossRefPubMed

10.

Wang L, Ren F, Wang Q, Baldridge LA, Monn MF, Fisher KW, Sheng W, Zhou X, Du X, Cheng L (2016) Significance of programmed death ligand 1 (PD-L1) immunohistochemical expression in colorectal cancer. Mol Diagn Ther 20(2):175–181. doi:10.1007/s40291-016-0188-1 CrossRefPubMed

11.

Lee LH, Cavalcanti MS, Segal NH, Hechtman JF, Weiser MR, Smith JJ, Garcia-Aguilar J, Sadot E, Ntiamoah P, Markowitz AJ, Shike M, Stadler ZK, Vakiani E, Klimstra DS, Shia J (2016) Patterns and prognostic relevance of PD-1 and PD-L1 expression in colorectal carcinoma. Mod Pathol 29(11):1433–1442. doi:10.1038/modpathol.2016.139 CrossRefPubMed

12.

Masugi Y, Nishihara R, Yang J, Mima K, da Silva A, Shi Y, Inamura K, Cao Y, Song M, Nowak JA, Liao X, Nosho K, Chan AT, Giannakis M, Bass AJ, Hodi FS, Freeman GJ, Rodig S, Fuchs CS, Qian ZR, Ogino S (2016) Tumour CD274 (PD-L1) expression and T cells in colorectal cancer. Gut. doi:10.1136/gutjnl-2016-311421

13.

Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS, Sosman JA, McDermott DF, Powderly JD, Gettinger SN, Kohrt HE, Horn L, Lawrence DP, Rost S, Leabman M, Xiao Y, Mokatrin A, Koeppen H, Hegde PS, Mellman I, Chen DS, Hodi FS (2014) Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515(7528):563–567. doi:10.1038/nature14011 CrossRefPubMedPubMedCentral

14.

Alexander J, Watanabe T, Wu TT, Rashid A, Li S, Hamilton SR (2001) Histopathological identification of colon cancer with microsatellite instability. Am J Pathol 158(2):527–535. doi:10.1016/S0002-9440(10)63994-6 CrossRefPubMedPubMedCentral

15.

Ilie M, Long-Mira E, Bence C, Butori C, Lassalle S, Bouhlel L, Fazzalari L, Zahaf K, Lalvee S, Washetine K, Mouroux J, Venissac N, Poudenx M, Otto J, Sabourin JC, Marquette CH, Hofman V, Hofman P (2016) Comparative study of the PD-L1 status between surgically resected specimens and matched biopsies of NSCLC patients reveal major discordances: a potential issue for anti-PD-L1 therapeutic strategies. Ann Oncol 27(1):147–153. doi:10.1093/annonc/mdv489 CrossRefPubMed

16.

Umar A, Boland CR, Terdiman JP, Syngal S, de la Chapelle A, Ruschoff J, Fishel R, Lindor NM, Burgart LJ, Hamelin R, Hamilton SR, Hiatt RA, Jass J, Lindblom A, Lynch HT, Peltomaki P, Ramsey SD, Rodriguez-Bigas MA, Vasen HF, Hawk ET, Barrett JC, Freedman AN, Srivastava S (2004) Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 96(4):261–268CrossRefPubMedPubMedCentral

17.

Lee HS, Cho SB, Lee HE, Kim MA, Kim JH, Park do J, Kim JH, Yang HK, Lee BL, Kim WH (2007) Protein expression profiling and molecular classification of gastric cancer by the tissue array method. Clin Cancer Res 13(14):4154–4163. doi:10.1158/1078-0432.ccr-07-0173 CrossRefPubMed

18.

Boland CR, Thibodeau SN, Hamilton SR, Sidransky D, Eshleman JR, Burt RW, Meltzer SJ, Rodriguez-Bigas MA, Fodde R, Ranzani GN, Srivastava S (1998) A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res 58(22):5248–5257PubMed

19.

Toon CW, Walsh MD, Chou A, Capper D, Clarkson A, Sioson L, Clarke S, Mead S, Walters RJ, Clendenning M, Rosty C, Young JP, Win AK, Hopper JL, Crook A, von Deimling A, Jenkins MA, Buchanan DD, Gill AJ (2013) BRAFV600E immunohistochemistry facilitates universal screening of colorectal cancers for Lynch syndrome. Am J Surg Pathol 37(10):1592–1602. doi:10.1097/PAS.0b013e31828f233d CrossRefPubMedPubMedCentral

20.

Nam SK, Yun S, Koh J, Kwak Y, Seo AN, Park KU, Kim DW, Kang SB, Kim WH, Lee HS (2016) BRAF, PIK3CA, and HER2 oncogenic alterations according to KRAS mutation status in advanced colorectal cancers with distant metastasis. PLoS One 11(3):e0151865. doi:10.1371/journal.pone.0151865 CrossRefPubMedPubMedCentral

21.

Greenhalgh T (1997) How to read a paper. Statistics for the non-statistician. I: Different types of data need different statistical tests. BMJ 315(7104):364–366CrossRefPubMedPubMedCentral

22.

Christine D, John R (2004) Statistics without maths for psychology: using SPSS for windows. Prentice Hall, London

23.

Capper D, Voigt A, Bozukova G, Ahadova A, Kickingereder P, von Deimling A, von Knebel Doeberitz M, Kloor M (2013) BRAF V600E-specific immunohistochemistry for the exclusion of Lynch syndrome in MSI-H colorectal cancer. Int J Cancer 133(7):1624–1630. doi:10.1002/ijc.28183 CrossRefPubMed

24.

Inaguma S, Lasota J, Wang Z, Felisiak-Golabek A, Ikeda H, Miettinen M (2017) Clinicopathologic profile, immunophenotype, and genotype of CD274 (PD-L1)-positive colorectal carcinomas. Mod Pathol 30(2):278–285. doi:10.1038/modpathol.2016.185 CrossRefPubMed

25.

Timmermann B, Kerick M, Roehr C, Fischer A, Isau M, Boerno ST, Wunderlich A, Barmeyer C, Seemann P, Koenig J, Lappe M, Kuss AW, Garshasbi M, Bertram L, Trappe K, Werber M, Herrmann BG, Zatloukal K, Lehrach H, Schweiger MR (2010) Somatic mutation profiles of MSI and MSS colorectal cancer identified by whole exome next generation sequencing and bioinformatics analysis. PLoS One 5(12):e15661. doi:10.1371/journal.pone.0015661 CrossRefPubMedPubMedCentral

26.

Giannakis M, Mu XJ, Shukla SA, Qian ZR, Cohen O, Nishihara R, Bahl S, Cao Y, Amin-Mansour A, Yamauchi M, Sukawa Y, Stewart C, Rosenberg M, Mima K, Inamura K, Nosho K, Nowak JA, Lawrence MS, Giovannucci EL, Chan AT, Ng K, Meyerhardt JA, Van Allen EM, Getz G, Gabriel SB, Lander ES, Wu CJ, Fuchs CS, Ogino S, Garraway LA (2016) Genomic correlates of immune-cell infiltrates in colorectal carcinoma. Cell Rep. doi:10.1016/j.celrep.2016.03.075 PubMedCentral

27.

Lal N, Beggs AD, Willcox BE, Middleton GW (2015) An immunogenomic stratification of colorectal cancer: implications for development of targeted immunotherapy. Oncoimmunology 4(3):e976052. doi:10.4161/2162402X.2014.976052 CrossRefPubMedPubMedCentral

28.

Boissiere-Michot F, Lazennec G, Frugier H, Jarlier M, Roca L, Duffour J, Du Paty E, Laune D, Blanchard F, Le Pessot F, Sabourin JC, Bibeau F (2014) Characterization of an adaptive immune response in microsatellite-instable colorectal cancer. Oncoimmunology 3:e29256. doi:10.4161/onci.29256 CrossRefPubMedPubMedCentral

29.

Llosa NJ, Cruise M, Tam A, Wicks EC, Hechenbleikner EM, Taube JM, Blosser RL, Fan H, Wang H, Luber BS, Zhang M, Papadopoulos N, Kinzler KW, Vogelstein B, Sears CL, Anders RA, Pardoll DM, Housseau F (2015) The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov 5(1):43–51. doi:10.1158/2159-8290.CD-14-0863 CrossRefPubMed

30.

Kim R, Emi M, Tanabe K (2007) Cancer immunoediting from immune surveillance to immune escape. Immunology 121(1):1–14. doi:10.1111/j.1365-2567.2007.02587.x CrossRefPubMedPubMedCentral

31.

Thompson ED, Zahurak M, Murphy A, Cornish T, Cuka N, Abdelfatah E, Yang S, Duncan M, Ahuja N, Taube JM, Anders RA, Kelly RJ (2016) Patterns of PD-L1 expression and CD8 T cell infiltration in gastric adenocarcinomas and associated immune stroma. Gut. doi:10.1136/gutjnl-2015-310839 PubMedCentral

32.

Heeren AM, Punt S, Bleeker MC, Gaarenstroom KN, van der Velden J, Kenter GG, de Gruijl TD, Jordanova ES (2016) Prognostic effect of different PD-L1 expression patterns in squamous cell carcinoma and adenocarcinoma of the cervix. Mod Pathol 29(7):753–763. doi:10.1038/modpathol.2016.64 CrossRefPubMedPubMedCentral

33.

Bellmunt J, Mullane SA, Werner L, Fay AP, Callea M, Leow JJ, Taplin ME, Choueiri TK, Hodi FS, Freeman GJ, Signoretti S (2015) Association of PD-L1 expression on tumor-infiltrating mononuclear cells and overall survival in patients with urothelial carcinoma. Ann Oncol 26(4):812–817. doi:10.1093/annonc/mdv009 CrossRefPubMed

34.

Zou MX, Peng AB, Lv GH, Wang XB, Li J, She XL, Jiang Y (2016) Expression of programmed death-1 ligand (PD-L1) in tumor-infiltrating lymphocytes is associated with favorable spinal chordoma prognosis. Am J Transl Res 8(7):3274–3287PubMedPubMedCentral

35.

Shigehiro Koganemaru NI, Miura 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 (2016) Prognostic value of programmed death-ligand 1 (PD-L1) expression in patients with stage III colorectal cancer. J Clin Oncol 34(suppl; abstr 3568) [Presented at the American Society of Clinical Oncology (ASCO) Annual Meeting 2016]

36.

He J, Hu Y, Hu M, Li B (2015) Development of PD-1/PD-L1 pathway in tumor immune microenvironment and treatment for non-small cell lung cancer. Sci Rep 5:13110. doi:10.1038/srep13110 CrossRefPubMedPubMedCentral

37.

Di Caro G, Marchesi F, Laghi L, Grizzi F (2013) Immune cells: plastic players along colorectal cancer progression. J Cell Mol Med 17(9):1088–1095. doi:10.1111/jcmm.12117 CrossRefPubMedPubMedCentral

38.

Madore J, Vilain RE, Menzies AM, Kakavand H, Wilmott JS, Hyman J, Yearley JH, Kefford RF, Thompson JF, Long GV, Hersey P, Scolyer RA (2015) PD-L1 expression in melanoma shows marked heterogeneity within and between patients: implications for anti-PD-1/PD-L1 clinical trials. Pigment Cell Melanoma Res 28(3):245–253. doi:10.1111/pcmr.12340 CrossRefPubMed

39.

Callea M, Albiges L, Gupta M, Cheng SC, Genega EM, Fay AP, Song J, Carvo I, Bhatt RS, Atkins MB, Hodi FS, Choueiri TK, McDermott DF, Freeman GJ, Signoretti S (2015) Differential expression of PD-L1 between primary and metastatic sites in clear-cell renal cell carcinoma. Cancer Immunol Res 3(10):1158–1164. doi:10.1158/2326-6066.CIR-15-0043 CrossRefPubMedPubMedCentral

40.

Barsoum IB, Smallwood CA, Siemens DR, Graham CH (2014) A mechanism of hypoxia-mediated escape from adaptive immunity in cancer cells. Cancer Res 74(3):665–674. doi:10.1158/0008-5472.CAN-13-0992 CrossRefPubMed

41.

Noman MZ, Desantis G, Janji B, Hasmim M, Karray S, Dessen P, Bronte V, Chouaib S (2014) PD-L1 is a novel direct target of HIF-1alpha, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J Exp Med 211(5):781–790. doi:10.1084/jem.20131916 CrossRefPubMedPubMedCentral

42.

Colussi D, Brandi G, Bazzoli F, Ricciardiello L (2013) Molecular pathways involved in colorectal cancer: implications for disease behavior and prevention. Int J Mol Sci 14(8):16365–16385. doi:10.3390/ijms140816365 CrossRefPubMedPubMedCentral

43.

Kocarnik JM, Shiovitz S, Phipps AI (2015) Molecular phenotypes of colorectal cancer and potential clinical applications. Gastroenterol Rep (Oxf) 3(4):269–276. doi:10.1093/gastro/gov046

44.

Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, Lee W, Yuan J, Wong P, Ho TS, Miller ML, Rekhtman N, Moreira AL, Ibrahim F, Bruggeman C, Gasmi B, Zappasodi R, Maeda Y, Sander C, Garon EB, Merghoub T, Wolchok JD, Schumacher TN, Chan TA (2015) Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348(6230):124–128. doi:10.1126/science.aaa1348 CrossRefPubMedPubMedCentral

45.

Azuma K, Ota K, Kawahara A, Hattori S, Iwama E, Harada T, Matsumoto K, Takayama K, Takamori S, Kage M, Hoshino T, Nakanishi Y, Okamoto I (2014) Association of PD-L1 overexpression with activating EGFR mutations in surgically resected nonsmall-cell lung cancer. Ann Oncol 25(10):1935–1940. doi:10.1093/annonc/mdu242 CrossRefPubMed

Title: Prognostic implication of CD274 (PD-L1) protein expression in tumor-infiltrating immune cells for microsatellite unstable and stable colorectal cancer
Authors: Kyu Sang Lee
Yoonjin Kwak
Soyeon Ahn
Eun Shin
Heung-Kwon Oh
Duck-Woo Kim
Sung-Bum Kang
Gheeyoung Choe
Woo Ho Kim
Hye Seung Lee
Publication date: 01-07-2017
Publisher: Springer Berlin Heidelberg
Published in: Cancer Immunology, Immunotherapy / Issue 7/2017
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-017-1999-6

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 7/2017

Cancer immunotherapy: how low-level ionizing radiation can play a key role

IDO and galectin-3 hamper the ex vivo generation of clinical grade tumor-specific T cells for adoptive cell therapy in metastatic melanoma

Programmed death-ligand 1 and its soluble form are highly expressed in nasal natural killer/T-cell lymphoma: a potential rationale for immunotherapy

A new peptide vaccine OCV-501: in vitro pharmacology and phase 1 study in patients with acute myeloid leukemia

Phase I/IIa clinical trial of a novel hTERT peptide vaccine in men with metastatic hormone-naive prostate cancer

HLA-DR expression in tumor epithelium is an independent prognostic indicator in esophageal adenocarcinoma patients

Keynote webinar | Spotlight on antibody–drug conjugates in cancer