DOI QR코드

DOI QR Code

Clinicopathologic significance of tumor microenvironment CD11c, and FOXP3 expression in diffuse large B-cell lymphoma patients receiving rituximab, cyclophosphamide, anthracycline, vincristine, and prednisone (R-CHOP) combination chemotherapy

  • Lee, Seul (Department of Internal Medicine, Dong-A University College of Medicine) ;
  • Kim, Dong Hyun (Department of Internal Medicine, Dong-A University College of Medicine) ;
  • Oh, Sung Yong (Department of Internal Medicine, Dong-A University College of Medicine) ;
  • Kim, So Yeon (Department of Internal Medicine, Dong-A University College of Medicine) ;
  • Koh, Myeong Seok (Department of Internal Medicine, Dong-A University College of Medicine) ;
  • Lee, Ji Hyun (Department of Internal Medicine, Dong-A University College of Medicine) ;
  • Lee, Suee (Department of Internal Medicine, Dong-A University College of Medicine) ;
  • Kim, Sung-Hyun (Department of Internal Medicine, Dong-A University College of Medicine) ;
  • Kwak, Jong-Young (Immune-Network Pioneer Research Center, Dong-A University College of Medicine) ;
  • Pak, Min Gyoung (Department of Pathology, Dong-A University College of Medicine) ;
  • Ju, Mi Ha (Immune-Network Pioneer Research Center, Dong-A University College of Medicine) ;
  • Kim, Hyo-Jin (Department of Internal Medicine, Dong-A University College of Medicine) ;
  • Jeong, Jin Sook (Immune-Network Pioneer Research Center, Dong-A University College of Medicine)
  • Received : 2015.06.07
  • Accepted : 2015.08.13
  • Published : 2017.03.01

Abstract

Background/Aims: CD11c is a dendritic cell marker in humans, which potentially induces a cytotoxic effect on lymphoma cells. Forkhead boxP3 (FOXP3) is a regulator of T lymphocyte in the microenvironment of the lymphoma. The principal objective of this study was to determine whether the tumors' microenvironment expressions of CD11c and FOXP3 are predictive of clinical outcomes in diffuse large B-cell lymphoma (DLBCL) patients receiving treatment with rituximab, cyclophosphamide, anthracycline, vincristine, and prednisone (R-CHOP) combination chemotherapy. Methods: The study population consisted of 100 patients with DLBCL. The CD11c and FOXP3 expression in primary tumors' microenvironment were evaluated using an immunohistochemistry (IHC). Results: CD11c and FOXP3 expression positivity in microenvironment were 25% and 35%, respectively. Each one counted for 1 point. In CD11c and FOXP3 stain, positive was counted as 0 and negative was 1. The points were separated into low risk (0 to 1) and high risk (2) groups. Only the extranodal DLBCL patient group analysis conveyed significant differences of progression-free survival (p = 0.019) and overall survival (p = 0.039) between the two groups. Conclusions: We can achieve possible clinical significance of lymphoma tumor microenvironments through CD11c and FOXP3 IHC stains in extranodal DLBCL patients receiving R-CHOP therapy.

Keywords

Acknowledgement

Supported by : National Research Foundation of Korea

References

  1. Coiffier B. Diffuse large cell lymphoma. Curr Opin Oncol 2001;13:325-334. https://doi.org/10.1097/00001622-200109000-00003
  2. Rossi D, Gaidano G. Molecular heterogeneity of diffuse large B-cell lymphoma: implications for disease management and prognosis. Hematology 2002;7:239-252. https://doi.org/10.1080/1024533021000024058
  3. Lenz G, Wright G, Dave SS, et al. Stromal gene signatures in large-B-cell lymphomas. N Engl J Med 2008;359:2313-2323. https://doi.org/10.1056/NEJMoa0802885
  4. Akay OM, Aras BD, Isiksoy S, et al. BCL2, BCL6, IGH, TP53, and MYC protein expression and gene rearrangements as prognostic markers in diffuse large B-cell lymphoma: a study of 44 Turkish patients. Cancer Genet 2014;207:87-93. https://doi.org/10.1016/j.cancergen.2014.02.001
  5. Liotta LA, Kohn EC. The microenvironment of the tumour-host interface. Nature 2001;411:375-379. https://doi.org/10.1038/35077241
  6. Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science 2011;331:1565-1570. https://doi.org/10.1126/science.1203486
  7. Fontenot JD, Rudensky AY. A well adapted regulatory contrivance: regulatory T cell development and the forkhead family transcription factor Foxp3. Nat Immunol 2005;6:331-337. https://doi.org/10.1038/ni1179
  8. Tzankov A, Meier C, Hirschmann P, Went P, Pileri SA, Dirnhofer S. Correlation of high numbers of intratumoral FOXP3+ regulatory T cells with improved survival in germinal center-like diffuse large B-cell lymphoma, follicular lymphoma and classical Hodgkin's lymphoma. Haematologica 2008;93:193-200. https://doi.org/10.3324/haematol.11702
  9. Beyer M, Schultze JL. Regulatory T cells in cancer. Blood 2006;108:804-811. https://doi.org/10.1182/blood-2006-02-002774
  10. Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature 1998;392:245-252. https://doi.org/10.1038/32588
  11. Banchereau J, Briere F, Caux C, et al. Immunobiology of dendritic cells. Annu Rev Immunol 2000;18:767-811. https://doi.org/10.1146/annurev.immunol.18.1.767
  12. Lanzavecchia A, Sallusto F. The instructive role of dendritic cells on T cell responses: lineages, plasticity and kinetics. Curr Opin Immunol 2001;13:291-298. https://doi.org/10.1016/S0952-7915(00)00218-1
  13. Gabrilovich D. Mechanisms and functional significance of tumour-induced dendritic-cell defects. Nat Rev Immunol 2004;4:941-952. https://doi.org/10.1038/nri1498
  14. Dubsky P, Ueno H, Piqueras B, Connolly J, Banchereau J, Palucka AK. Human dendritic cell subsets for vaccination. J Clin Immunol 2005;25:551-572. https://doi.org/10.1007/s10875-005-8216-7
  15. Steinman RM, Banchereau J. Taking dendritic cells into medicine. Nature 2007;449:419-426. https://doi.org/10.1038/nature06175
  16. Palucka K, Banchereau J, Mellman I. Designing vaccines based on biology of human dendritic cell subsets. Immunity 2010;33:464-478. https://doi.org/10.1016/j.immuni.2010.10.007
  17. Shortman K, Liu YJ. Mouse and human dendritic cell subtypes. Nat Rev Immunol 2002;2:151-161. https://doi.org/10.1038/nri746
  18. Spits H, Lanier LL. Natural killer or dendritic: what's in a name? Immunity 2007;26:11-16. https://doi.org/10.1016/j.immuni.2007.01.004
  19. Campo E, Swerdlow SH, Harris NL, Pileri S, Stein H, Jaffe ES. The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications. Blood 2011;117:5019-5032. https://doi.org/10.1182/blood-2011-01-293050
  20. Hans CP, Weisenburger DD, Greiner TC, et al. Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood 2004;103:275-282. https://doi.org/10.1182/blood-2003-05-1545
  21. Sweetenham JW. Diffuse large B-cell lymphoma: risk stratification and management of relapsed disease. Hematology Am Soc Hematol Educ Program 2005:252-259.
  22. Alizadeh AA, Eisen MB, Davis RE, et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 2000;403:503-511. https://doi.org/10.1038/35000501
  23. Shiozawa E, Yamochi-Onizuka T, Takimoto M, Ota H. The GCB subtype of diffuse large B-cell lymphoma is less frequent in Asian countries. Leuk Res 2007;31:1579-1583. https://doi.org/10.1016/j.leukres.2007.03.017
  24. Hwang HS, Yoon DH, Suh C, Park CS, Huh J. Prognostic value of immunohistochemical algorithms in gastrointestinal diffuse large B-cell lymphoma. Blood Res 2013;48:266-273. https://doi.org/10.5045/br.2013.48.4.266
  25. Lopez-Guillermo A, Colomo L, Jimenez M, et al. Diffuse large B-cell lymphoma: clinical and biological characterization and outcome according to the nodal or extranodal primary origin. J Clin Oncol 2005;23:2797-2804. https://doi.org/10.1200/JCO.2005.07.155
  26. Abramson JS, Shipp MA. Advances in the biology and therapy of diffuse large B-cell lymphoma: moving toward a molecularly targeted approach. Blood 2005;106:1164-1174. https://doi.org/10.1182/blood-2005-02-0687
  27. Moller MB, Pedersen NT, Christensen BE. Diffuse large B-cell lymphoma: clinical implications of extranodal versus nodal presentation: a population-based study of 1575 cases. Br J Haematol 2004;124:151-159. https://doi.org/10.1046/j.1365-2141.2003.04749.x
  28. d'Amore F, Christensen BE, Brincker H, et al. Clinicopathological features and prognostic factors in extranodal non-Hodgkin lymphomas. Danish LYFO Study Group. Eur J Cancer 1991;27:1201-1208. https://doi.org/10.1016/0277-5379(91)90081-N
  29. Houldsworth J, Mathew S, Rao PH, et al. REL proto-oncogene is frequently amplified in extranodal diffuse large cell lymphoma. Blood 1996;87:25-29.
  30. Gronbaek K, Straten PT, Ralfkiaer E, et al. Somatic Fas mutations in non-Hodgkin's lymphoma: association with extranodal disease and autoimmunity. Blood 1998;92:3018-3024.
  31. Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25): breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 1995;155:1151-1164.
  32. Li B, Samanta A, Song X, et al. FOXP3 ensembles in T-cell regulation. Immunol Rev 2006;212:99-113. https://doi.org/10.1111/j.0105-2896.2006.00405.x
  33. Coutinho R, Clear AJ, Mazzola E, et al. Revisiting the immune microenvironment of diffuse large B-cell lymphoma using a tissue microarray and immunohistochemistry: robust semi-automated analysis reveals CD3 and FoxP3 as potential predictors of response to R-CHOP. Haematologica 2015;100:363-369. https://doi.org/10.3324/haematol.2014.110189
  34. Lee NR, Song EK, Jang KY, et al. Prognostic impact of tumor infiltrating FOXP3 positive regulatory T cells in diffuse large B-cell lymphoma at diagnosis. Leuk Lymphoma 2008;49:247-256. https://doi.org/10.1080/10428190701824536
  35. Shurin MR, Shurin GV, Lokshin A, et al. Intratumoral cytokines/chemokines/growth factors and tumor infiltrating dendritic cells: friends or enemies? Cancer Metastasis Rev 2006;25:333-356. https://doi.org/10.1007/s10555-006-9010-6
  36. Middle S, Coupland SE, Taktak A, et al. Immunohistochemical analysis indicates that the anatomical location of B-cell non-Hodgkin's lymphoma is determined by differentially expressed chemokine receptors, sphingosine-1-phosphate receptors and integrins. Exp Hematol Oncol 2015;4:10. https://doi.org/10.1186/s40164-015-0004-3
  37. Upadhyay R, Hammerich L, Peng P, Brown B, Merad M, Brody JD. Lymphoma: immune evasion strategies. Cancers (Basel) 2015;7:736-762. https://doi.org/10.3390/cancers7020736

Cited by

  1. Inflammatory Cells in Diffuse Large B Cell Lymphoma vol.9, pp.8, 2020, https://doi.org/10.3390/jcm9082418