Programmed death 1 ligand (PD-L1) is an immunomodulatory molecule expressed by cancer cells, and it has been widely demonstrated to inhibit host antitumor responses. The aim of the present study was to identify clinicopathological features associated with PD-L1 expression in the secondary solid cancers of patients after allogeneic hematopoietic stem cell transplantation. In this database of 530 patients who received allo-HSCT between 1990 and 2017, 15 developed solid cancers with a median interval of 3487 days after transplantation. Three patients had 2 different solid cancers. Eighteen solid cancer cases were identified. A multivariate analysis showed that chronic graft-versus-host disease (GVHD) was associated with an increased risk of solid cancer. The presence of chronic GVHD was observed in 8 out of 18 cases at the diagnosis of secondary malignancies. PD-L1 expression levels in cancers were significantly higher in patients with active chronic GVHD than in those without chronic GVHD (P = 0.020). Five cases of cancer that developed in the involved organs of chronic GVHD showed 30% or higher PD-L1 positivity. The present results revealed distinct PD-L1 expression in the secondary solid cancers of post-transplant patients with chronic GVHD.
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Copelan EA. Hematopoietic stem-cell transplantation. N Engl J Med. 2006;354:1813–26.
Gooley TA, Chien JW, Pergam SA, Hingorani S, Sorror ML, Boeckh M, et al. Reduced mortality after allogeneic hematopoietic-cell transplantation. N Engl J Med. 2010;363:2091–101.
Hahn T, McCarthy PL Jr, Hassebroek A, Bredeson C, Gajewski JL, Hale GA, et al. Significant improvement in survival after allogeneic hematopoietic cell transplantation during a period of significantly increased use, older recipient age, and use of unrelated donors. J Clin Oncol. 2013;31:2437–49.
Curtis RE, Rowlings PA, Deeg HJ, Shriner DA, Socíe G, Travis LB, et al. Solid cancers after bone marrow transplantation. N Engl J Med. 1997;336:897–904.
Bhatia S, Louie AD, Bhatia R, O'Donnell MR, Fung H, Kashyap A, et al. Solid cancers after bone marrow transplantation. J Clin Oncol. 2001;19:464–71.
Baker KS, DeFor TE, Burns LJ, Ramsay NK, Neglia JP, Robison LL. New malignancies after blood or marrow stem-cell transplantation in children and adults: incidence and risk factors. J Clin Oncol. 2003;21:1352–8.
Majhail NS, Brazauskas R, Rizzo JD, Sobecks RM, Wang Z, Horowitz MM, et al. Secondary solid cancers after allogeneic hematopoietic cell transplantation using busulfan-cyclophosphamide conditioning. Blood. 2011;117:316–22.
Rizzo JD, Curtis RE, Socié G, Sobocinski KA, Gilbert E, Landgren O, et al. Solid cancers after allogeneic hematopoietic cell transplantation. Blood. 2009;113:1175–83.
Atsuta Y, Suzuki R, Yamashita T, Fukuda T, Miyamura K, Taniguchi S, et al. Continuing increased risk of oral/esophageal cancer after allogeneic hematopoietic stem cell transplantation in adults in association with chronic graft-versus-host disease. Ann Oncol. 2014;25:435–41.
Shimada K, Yokozawa T, Atsuta Y, Kohno A, Maruyama F, Yano K, et al. Solid tumors after hematopoietic stem cell transplantation in Japan: incidence, risk factors and prognosis. Bone Marrow Transplant. 2005;36:115–21.
Yokota A, Ozawa S, Masanori T, Akiyama H, Ohshima K, Kanda Y, et al. Secondary solid tumors after allogeneic hematopoietic SCT in Japan. Bone Marrow Transplant. 2012;47:95–100.
Vajdic CM, Mayson E, Dodds AJ, O'Brien T, Wilcox L, Nivison-Smith I, et al. Second cancer risk and late mortality in adult Australians receiving allogeneic hematopoietic stem cell transplantation: a population-based cohort study. Biol Blood Marrow Transplant. 2016;22:949–56.
Atsuta Y, Hirakawa A, Nakasone H, Kurosawa S, Oshima K, Sakai R, et al. Late mortality and causes of death among long-term survivors after allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2016;22:1702–9.
Curtis RE, Metayer C, Rizzo JD, Socié G, Sobocinski KA, Flowers ME, et al. Impact of chronic GVHD therapy on the development of squamous-cell cancers after hematopoietic stem-cell transplantation: an international case-control study. Blood. 2005;105:3802–11.
Majhail NS. Secondary cancers following allogeneic haematopoietic cell transplantation in adults. Br J Haematol. 2011;154:301–10.
Croci DO, Zacarías Fluck MF, Rico MJ, Matar P, Rabinovich GA, Scharovsky OG. Dynamic cross-talk between tumor and immune cells in orchestrating the immunosuppressive network at the tumor microenvironment. Cancer Immunol Immunother. 2007;56:1687–700.
Blank C, Mackensen A. Contribution of the PD-L1/PD-1 pathway to T-cell exhaustion: an update on implications for chronic infections and tumor evasion. Cancer Immunol Immunother. 2007;56:739–45.
Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677–704.
Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci USA. 2002;99:12293–7.
Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443–544.
Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366:2455–65.
Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell. 2015;27:450–61.
Page DB, Postow MA, Callahan MK, Allison JP, Wolchok JD. Immune modulation in cancer with antibodies. Annu Rev Med. 2014;65:185–202.
Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N Engl J Med. 2015;372:311–9.
Hughes T, Adler A, Kelly JA, Kaufman KM, Williams AH, Langefeld CD, et al. Evidence for gene-gene epistatic interactions among susceptibility loci for systemic lupus erythematosus. Arthritis Rheum. 2012;64:485–92.
Prokunina L, Castillejo-López C, Oberg F, Gunnarsson I, Berg L, Magnusson V, et al. A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans. Nat Genet. 2002;32:666–9.
Thorburn CM, Prokunina-Olsson L, Sterba KA, Lum RF, Seldin MF, Alarcon-Riquelme ME, et al. Association of PDCD1 genetic variation with risk and clinical manifestations of systemic lupus erythematosus in a multiethnic cohort. Genes Immun. 2007;8:279–87.
Liu JL, Zhang FY, Liang YH, Xiao FL, Zhang SQ, Cheng YL, et al. Association between the PD1.3A/G polymorphism of the PDCD1 gene and systemic lupus erythematosus in European populations: a meta-analysis. J Eur Acad Dermatol Venereol. 2009;23:425–32.
Kong EK, Prokunina-Olsson L, Wong WH, Lau CS, Chan TM, Alarcón-Riquelme M, et al. A new haplotype of PDCD1 is associated with rheumatoid arthritis in Hong Kong Chinese. Arthritis Rheum. 2005;52:1058–62.
Prokunina L, Padyukov L, Bennet A, de Faire U, Wiman B, Prince J, et al. Association of the PD-1.3A allele of the PDCD1 gene in patients with rheumatoid arthritis negative for rheumatoid factor and the shared epitope. Arthritis Rheum. 2004;50:1770–3.
Nielsen C, Hansen D, Husby S, Jacobsen BB, Lillevang ST. Association of a putative regulatory polymorphism in the PD-1 gene with susceptibility to type 1 diabetes. Tissue Antigens. 2003;62:492–7.
Ni R, Ihara K, Miyako K, Kuromaru R, Inuo M, Kohno H, et al. PD-1 gene haplotype is associated with the development of type 1 diabetes mellitus in Japanese children. Hum Genet. 2007;121:223–32.
Juchem KW, Sacirbegovic F, Zhang C, Sharpe AH, Russell K, McNiff JM, et al. PD-L1 prevents the development of autoimmune heart disease in graft-versus-host disease. J Immunol. 2018;200:834–46.
Saha A, Aoyama K, Taylor PA, Koehn BH, Veenstra RG, Panoskaltsis-Mortari A, et al. Host programmed death ligand 1 is dominant over programmed death ligand 2 expression in regulating graft-versus-host disease lethality. Blood. 2013;122:3062–73.
Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015;373:1627–39.
Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WE, Poddubskaya E, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015;373:123–35.
Ferris RL, Blumenschein G Jr, Fayette J, Guigay J, Colevas AD, Licitra L, et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med. 2016;375:1856–67.
Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, et al. Nivolumab versus Everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373:1803–13.
Fakhry C, Lacchetti C, Rooper LM, Jordan RC, Rischin D, Sturgis EM, et al. Human papillomavirus testing in head and neck carcinomas: ASCO clinical practice guideline endorsement of the college of American Pathologists Guideline. J Clin Oncol. 2018;36(31):3152–61.
Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, et al. 1994 consensus conference on acute GVHD grading. Bone Marrow Transplant. 1995;15:825–8.
Sullivan KM, Agura E, Anasetti C, Appelbaum F, Badger C, Bearman S, et al. Chronic graft-versus-host disease and other late complications of bone marrow transplantation. Semin Hematol. 1991;28:250–9.
Giralt S, Ballen K, Rizzo D, Bacigalupo A, Horowitz M, Pasquini M, et al. Reduced-intensity conditioning regimen workshop: defining the dose spectrum. Report of a workshop convened by the center for international blood and marrow transplant research. Biol Blood Marrow Transplant. 2009;15:367–9.
Salgado R, Denkert C, Demaria S, Sirtaine N, Klauschen F, Pruneri G, et al. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol. 2015;26(2):259–71.
Yokoyama S, Miyoshi H, Nakashima K, Shimono J, Hashiguchi T, Mitsuoka M, et al. Prognostic value of programmed death ligand 1 and programmed death 1 expression in thymic carcinoma. Clin Cancer Res. 2016;22(18):4727–34.
Shimura S, Yang G, Ebara S, Wheeler TM, Frolov A, Thompson TC. Reduced infiltration of tumor-associated macrophages in human prostate cancer: association with cancer progression. Cancer Res. 2000;60(20):5857–61.
Miyoshi H, Kiyasu J, Kato T, Yoshida N, Shimono J, Yokoyama S, et al. PD-L1 expression on neoplastic or stromal cells is respectively a poor or good prognostic factor for adult t-cell leukemia/lymphoma. Blood. 2016;128(10):1374–81.
Kazama R, Miyoshi H, Takeuchi M, Miyawaki K, Nakashima K, Yoshida N, et al. Combination of CD47 and SIRPα constituting the "Don't Eat Me Signal" is a prognostic factor in diffuse large b-cell lymphoma. Cancer Sci. 2020. https://doi.org/10.1111/cas.14437.
Gooley TA, Leisenring W, Crowley J, Storer BE. Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Stat Med. 1999;18:695–706.
Fine JP, Gray RJ. A proportional hazards model for subdistribution of a competing risk. J Am Stat Assoc. 1999;94:496–509.
Kanda Y. Investigation of the freely available easy-to-use software 'EZR' for medical statistics. Bone Marrow Transplant. 2013;48:452–8.
Santoiemma PP, Powell DJ Jr. Tumor infiltrating lymphocytes in ovarian cancer. Cancer Biol Ther. 2015;16(6):807–20.
Bremnes RM, Busund LT, Kilvær TL, Andersen S, Richardsen E, Paulsen EE, et al. The role of tumor-infiltrating lymphocytes in development, progression, and prognosis of non-small cell lung cancer. J Thorac Oncol. 2016;11(6):789–800.
Denkert C, von Minckwitz G, Darb-Esfahani S, Lederer B, Heppner BI, Weber KE, et al. Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: a pooled analysis of 3771 patients treated with neoadjuvant therapy. Lancet Oncol. 2018;19(1):40–50.
Harada K, Dong X, Estrella JS, Correa AM, Xu Y, Hofstetter WL, et al. Tumor-associated macrophage infiltration is highly associated with PD-L1 expression in gastric adenocarcinoma. Gastric Cancer. 2018;21:31–40.
Kuang DM, Zhao Q, Peng C, Xu J, Zhang JP, Wu C, Zheng L. Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-L1. J Exp Med. 2009;206(6):1327–37.
Kataoka K, Shiraishi Y, Takeda Y, Sakata S, Matsumoto M, Nagano S, et al. Aberrant PD-L1 expression through 3'-UTR disruption in multiple cancers. Nature. 2016;534:402–6.
Lyford-Pike S, Peng S, Young GD, Taube JM, Westra WH, Akpeng B, et al. Evidence for a role of the PD-1:PD-L1 pathway in immune resistance of HPV-associated head and neck squamous cell carcinoma. Cancer Res. 2013;73:1733–41.
Syrjänen S. Human papillomavirus (HPV) in head and neck cancer. J Clin Virol. 2005;32:S59–S66.
Miller CS, Johnstone BM. Human papillomavirus as a risk factor for oral squamous cell carcinoma: a meta-analysis, 1982–1997. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2001;91:622–35.
Howley PM, Pfister HJ. Beta genus papillomaviruses and skin cancer. Virology. 2015;479–480:290–6.
Hufbauer M, Akgül B. Molecular mechanisms of human papillomavirus induced skin carcinogenesis. Viruses. 2017;9(7):187.
Yang YG, Wang H, Asavaroengchai W, Dey BR. Role of interferon-gamma in GVHD and GVL. Cell Mol Immunol. 2005;2(5):323–9.
Taube JM, Anders RA, Young GD, Xu H, Sharma R, McMiller TL, et al. Colocalization of inflammatory response with B7–h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl Med. 2012;4:127–37.
The authors thank the many hematologists at Department of Hematology, Atomic Bomb Disease and Hibakusha Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University, for the diagnosis and treatment of post-transplant patients with solid cancers. This work was partly supported by the grant from Japan Society for the Promotion of Science (JSPS) KAKENHI Grant-in Aid for Young Scientists (B) (#17K16189) for H.I..
This study was approved by the Ethics Committees of Nagasaki University Hospital (approval no. 18052108–4), Sasebo City General Hospital (approval no. 2018-A020), the National Hospital Organization Nagasaki Medical Center (approval no. 30034), and Nagasaki Prefecture Gotochuoh Hospital (approval no. 30–4) at which this study was performed.
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Kasai, S., Itonaga, H., Niino, D. et al. Programmed death 1 ligand (PD-L1) in solid cancers after allogeneic hematopoietic stem cell transplantation: a retrospective analysis by the Nagasaki Transplant Group. Int J Hematol (2020). https://doi.org/10.1007/s12185-020-02926-6
- Allogeneic transplantation
- Graft-versus-host disease
- Hematopoietic stem cell transplantation
- Second cancer