Indoleamine 2,3-dioxygenase (IDO) is frequently expressed in stromal cells of Hodgkin lymphoma and is associated with adverse clinical features: a retrospective cohort study

BMC Cancer

Ji-Young Choe⁶  Ji Yun Yun⁶  Yoon Kyoung Jeon³  Se Hoon Kim⁵  Gyeongsin Park⁴  Joo Ryoung Huh²  Sohee Oh⁷  Ji Eun Kim¹ 

[1] Department of Pathology, Seoul National University Boramae Hospital, Seoul, Korea

[2] Department of Pathology, Asan Medical Center, Seoul, Korea

[3] Department of Pathology, Seoul National University Hospital, Seoul, Korea

[4] Department of Pathology, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, Korea

[5] Department of Pathology, Yonsei University College of Medicine, Seoul, Korea

[6] Department of Pathology, Seoul National University Bundang Hospital, Seongnam-si, Korea

[7] Department of Biostatistics, Seoul National University Boramae Hospital, Seoul, Korea

关键词: Pathology;    Epstein-barr virus infections;    Tumor microenvironment;    Stromal cells;    Macrophages;    Indoleamine-pyrrole 2,3-dioxygenase;    Hodgkin disease;   

Others  :  858823
DOI  :  10.1186/1471-2407-14-335

 received in 2013-09-02, accepted in 2014-05-02,  发布年份 2014

【 摘 要 】

Background

Regulation of tumor microenvironment is closely involved in the prognosis of Hodgkin lymphoma (HL). Indoleamine 2,3-dioxygenase (IDO) is an enzyme acting as immune modulator through suppression of T-cell immunity. This study aims to investigate role of IDO in the microenvironment of HL.

Methods

A total of 121 cases of HL were enrolled to do immunohistochemistry for IDO, CD163, CD68, CD4, CD8, and FoxP3. Positivity was evaluated from area fractions or numbers of positive cells using automated image analyzer. Correlations between IDO expression and various cellular infiltrates and clinicopathologic parameters were examined and survival analyses were performed.

Results

IDO was expressed in histiocytes, dendritic cells and some endothelial cells with variable degrees, but not in tumor cells. IDO positive cells were more frequently found in mixed cellularity type than other histologic types, and in cases with EBV+, high Ann Arbor stages, B symptoms, and high IPS (all p < 0.05). High IDO expression was associated with inferior survival (p < 0.001) and reflects an independent prognostic factor in nodular sclerosis HL.

Conclusions

This is the first study suggesting that IDO is the principle immunomodulator and is involved to adverse clinical outcomes of HL.

【 授权许可】

   
2014 Choe et al.; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Herreros B, Sanchez-Aguilera A, Piris MA: Lymphoma microenvironment: culprit or innocent? Leukemia 2008, 22:49-58.
• [2]Steidl C, Connors JM, Gascoyne RD: Molecular pathogenesis of Hodgkin’s lymphoma: increasing evidence of the importance of the microenvironment. J Clin Oncol 2011, 29:1812-1826.
• [3]Wilke CM, Zou W: T lymphocytes to IDO + cells: check. Blood 2011, 117:2082-2083.
• [4]Curti A, Trabanelli S, Salvestrini V, Baccarani M, Lemoli RM: The role of indoleamine 2,3-dioxygenase in the induction of immune tolerance: focus on hematology. Blood 2009, 113:2394-2401.
• [5]Puccetti P, Grohmann U: IDO and regulatory T cells: a role for reverse signalling and non-canonical NF-kappaB activation. Nat Rev Immunol 2007, 7:817-823.
• [6]Andersen MH: The specific targeting of immune regulation: T-cell responses against indoleamine 2,3-dioxygenase. Cancer Immunol Immunother 2012, 61:1289-1297.
• [7]Godin-Ethier J, Hanafi LA, Piccirillo CA, Lapointe R: Indoleamine 2,3-dioxygenase expression in human cancers: clinical and immunologic perspectives. Clin Cancer Res 2011, 17:6985-6991.
• [8]Ino K, Yamamoto E, Shibata K, Kajiyama H, Yoshida N, Terauchi M, Nawa A, Nagasaka T, Takikawa O, Kikkawa F: Inverse correlation between tumoral indoleamine 2,3-dioxygenase expression and tumor-infiltrating lymphocytes in endometrial cancer: its association with disease progression and survival. Clin Cancer Res 2008, 14:2310-2317.
• [9]Inaba T, Ino K, Kajiyama H, Yamamoto E, Shibata K, Nawa A, Nagasaka T, Akimoto H, Takikawa O, Kikkawa F: Role of the immunosuppressive enzyme indoleamine 2,3-dioxygenase in the progression of ovarian carcinoma. Gynecol Oncol 2009, 115:185-192.
• [10]Lee JR: Pattern of recruitment of immunoregulatory antigen-presenting cells in malignant melanoma. Lab Invest 2003, 83:1457-1466.
• [11]Ninomiya S, Hara T, Tsurumi H, Hoshi M, Kanemura N, Goto N, Kasahara S, Shimizu M, Ito H, Saito K, Hirose Y, Yamada T, Takahashi T, Seishima M, Takami T, Moriwaki H: Indoleamine 2,3-dioxygenase in tumor tissue indicates prognosis in patients with diffuse large B-cell lymphoma treated with R-CHOP. Ann Hematol 2011, 90:409-416.
• [12]Steidl C, Lee T, Shah SP, Farinha P, Han G, Nayar T, Delaney A, Jones SJ, Iqbal J, Weisenburger DD, Bast MA, Rosenwald A, Muller-Hermelink HK, Rimsza LM, Campo E, Delabie J, Braziel RM, Cook JR, Tubbs RR, Jaffe ES, Lenz G, Connors JM, Staudt LM, Chan WC, Gascoyne RD: Tumor-associated macrophages and survival in classic Hodgkin’s lymphoma. N Engl J Med 2010, 362:875-885.
• [13]Kamper P, Bendix K, Hamilton-Dutoit S, Honore B, Nyengaard JR, D’Amore F: Tumor-infiltrating macrophages correlate with adverse prognosis and Epstein-Barr virus status in classical Hodgkin’s lymphoma. Haematologica 2011, 96:269-276.
• [14]Zaki MA, Wada N, Ikeda J, Shibayama H, Hashimoto K, Yamagami T, Tatsumi Y, Tsukaguchi M, Take H, Tsudo M, Morii E, Aozasa K: Prognostic implication of types of tumor-associated macrophages in Hodgkin lymphoma. Virchows Arch 2011, 459:361-366.
• [15]Tzankov A, Matter MS, Dirnhofer S: Refined prognostic role of CD68-positive tumor macrophages in the context of the cellular micromilieu of classical Hodgkin lymphoma. Pathobiology 2010, 77:301-308.
• [16]Greaves P, Clear A, Coutinho R, Wilson A, Matthews J, Owen A, Shanyinde M, Lister TA, Calaminici M, Gribben JG: Expression of FOXP3, CD68, and CD20 at diagnosis in the microenvironment of classical Hodgkin lymphoma is predictive of outcome. J Clin Oncol 2013, 31:256-262.
• [17]Elpek KG, Lacelle C, Singh NP, Yolcu ES, Shirwan H: CD4 + CD25+ T regulatory cells dominate multiple immune evasion mechanisms in early but not late phases of tumor development in a B cell lymphoma model. J Immunol 2007, 178:6840-6848.
• [18]Koh YW, Yoon DH, Suh C, Huh J: Impact of the Epstein-Barr virus positivity on Hodgkin’s lymphoma in a large cohort from a single institute in Korea. Ann Hematol 2012, 91:1403-1412.
• [19]Kennedy-Nasser AA, Hanley P, Bollard CM: Hodgkin disease and the role of the immune system. Pediatr Hematol Oncol 2011, 28:176-186.
• [20]Song H, Park H, Kim J, Park G, Kim YS, Kim SM, Kim D, Seo SK, Lee HK, Cho D, Hur D: IDO metabolite produced by EBV-transformed B cells inhibits surface expression of NKG2D in NK cells via the c-Jun N-terminal kinase (JNK) pathway. Immunol Lett 2011, 136:187-193.
• [21]Manches O, Fernandez MV, Plumas J, Chaperot L, Bhardwaj N: Activation of the noncanonical NF-kappaB pathway by HIV controls a dendritic cell immunoregulatory phenotype. Proc Natl Acad Sci U S A 2012, 109:14122-14127.