Skip to main content
Erschienen in: International Journal of Hematology 3/2018

10.05.2018 | Original Article

CD3+/CD8+ T-cell density and tumoral PD-L1 predict survival irrespective of rituximab treatment in Chinese diffuse large B-cell lymphoma patients

verfasst von: Yunfei Shi, Lijuan Deng, Yuqin Song, Dongmei Lin, Yumei Lai, LiXin Zhou, Lei Yang, Xianghong Li

Erschienen in: International Journal of Hematology | Ausgabe 3/2018

Einloggen, um Zugang zu erhalten

Abstract

To investigate the prognostic value of tumor-infiltrating T-cell density and programmed cell death ligand-1 (PD-L1) expression in diffuse large B cell lymphoma (DLBCL). One-hundred-twenty-five Chinese DLBCL patients were enrolled in our study and provided samples; 76 of all cases were treated with rituximab (R). Tumor tissues were immunostained and analyzed for CD3+ and CD8+ tumor-infiltrating T-cell density, tumoral PD-L1, and microenvironmental PD-L1 (mPD-L1). The density of CD3 was rated as high in 33.6% cases, while 64.0% of DLBCLs were classified as high CD8 density. Of all cases, 16.8% were PD-L1+. Of the remaining PD-L1–DLBCLs, 29.8% positively expressed mPD-L1. Both CD3 high density and CD8 high density were associated with mPD-L1 positivity (P = 0.001 and P = 0.0001). In multivariate analysis, independently, high CD3 density predicted better OS (P = 0.023), while CD8 high density and PD-L1 positivity were both associated with prolonged PFS (P = 0.013 and P = 0.036, respectively). Even in the subgroup treated with R, univariate analyses indicated that high CD3 density and PD-L1 positivity were associated with better OS (P = 0.041) and PFS (P = 0.033), respectively. The infiltrating densities of CD3+ T-cells, CD8+ T-cells, and PD-L1 expression are predictive of survival in DLBCLs, irrespective of R usage.
Anhänge
Nur mit Berechtigung zugänglich
Literatur
1.
Zurück zum Zitat Zhou Z, Sehn LH, Rademaker AW, Gordon LI, Lacasce AS, Crosby-Thompson A, et al. An enhanced International Prognostic Index (NCCN-IPI) for patients with diffuse large B-cell lymphoma treated in the rituximab era. Blood. 2014;123:837 – 42.CrossRefPubMedPubMedCentral Zhou Z, Sehn LH, Rademaker AW, Gordon LI, Lacasce AS, Crosby-Thompson A, et al. An enhanced International Prognostic Index (NCCN-IPI) for patients with diffuse large B-cell lymphoma treated in the rituximab era. Blood. 2014;123:837 – 42.CrossRefPubMedPubMedCentral
2.
Zurück zum Zitat Hans CP, Weisenburger DD, Greiner TC, Gascoyne RD, Delabie J, Ott G, et al. Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood. 2004;103:275 – 82.CrossRefPubMed Hans CP, Weisenburger DD, Greiner TC, Gascoyne RD, Delabie J, Ott G, et al. Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood. 2004;103:275 – 82.CrossRefPubMed
3.
Zurück zum Zitat Green TM, Young KH, Visco C, Xu-Monette ZY, Orazi A, Go RS, et al. Immunohistochemical double-hit score is a strong predictor of outcome in patients with diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol. 2012;30:3460–7.CrossRefPubMed Green TM, Young KH, Visco C, Xu-Monette ZY, Orazi A, Go RS, et al. Immunohistochemical double-hit score is a strong predictor of outcome in patients with diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol. 2012;30:3460–7.CrossRefPubMed
4.
Zurück zum Zitat Meyer PN, Fu K, Greiner TC, Smith LM, Delabie J, Gascoyne RD, et al. Immunohistochemical methods for predicting cell of origin and survival in patients with diffuse large B-cell lymphoma treated with rituximab. J Clin Oncol. 2011;29:200–7.CrossRefPubMed Meyer PN, Fu K, Greiner TC, Smith LM, Delabie J, Gascoyne RD, et al. Immunohistochemical methods for predicting cell of origin and survival in patients with diffuse large B-cell lymphoma treated with rituximab. J Clin Oncol. 2011;29:200–7.CrossRefPubMed
5.
Zurück zum Zitat Johnson NA, Slack GW, Savage KJ, Connors JM, Ben-Neriah S, Rogic S, et al. Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol. 2012;30:3452–9.CrossRefPubMedPubMedCentral Johnson NA, Slack GW, Savage KJ, Connors JM, Ben-Neriah S, Rogic S, et al. Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol. 2012;30:3452–9.CrossRefPubMedPubMedCentral
6.
Zurück zum Zitat Kiyasu J, Miyoshi H, Hirata A, Arakawa F, Ichikawa A, Niino D, et al. Expression of programmed cell death ligand 1 is associated with poor overall survival in patients with diffuse large B-cell lymphoma. Blood. 2015;126:2193–201.CrossRefPubMedPubMedCentral Kiyasu J, Miyoshi H, Hirata A, Arakawa F, Ichikawa A, Niino D, et al. Expression of programmed cell death ligand 1 is associated with poor overall survival in patients with diffuse large B-cell lymphoma. Blood. 2015;126:2193–201.CrossRefPubMedPubMedCentral
8.
Zurück zum Zitat Xing W, Dresser K, Zhang R, Evens AM, Yu H, Woda BA, et al. PD-L1 expression in EBV-negative diffuse large B-cell lymphoma: clinicopathologic features and prognostic implications. Oncotarget. 2016;7:59976–86.PubMedPubMedCentral Xing W, Dresser K, Zhang R, Evens AM, Yu H, Woda BA, et al. PD-L1 expression in EBV-negative diffuse large B-cell lymphoma: clinicopathologic features and prognostic implications. Oncotarget. 2016;7:59976–86.PubMedPubMedCentral
9.
Zurück zum Zitat Becht E, Giraldo NA, Germain C, de Reynies A, Laurent-Puig P, Zucman-Rossi J, et al. Immune contexture, immunoscore, and malignant cell molecular subgroups for prognostic and theranostic classifications of cancers. Adv Immunol. 2016;130:95–190.CrossRefPubMed Becht E, Giraldo NA, Germain C, de Reynies A, Laurent-Puig P, Zucman-Rossi J, et al. Immune contexture, immunoscore, and malignant cell molecular subgroups for prognostic and theranostic classifications of cancers. Adv Immunol. 2016;130:95–190.CrossRefPubMed
10.
Zurück zum Zitat Galon J, Fox BA, Bifulco CB, Masucci G, Rau T, Botti G, et al. Immunoscore and Immunoprofiling in cancer: an update from the melanoma and immunotherapy bridge 2015. J Transl Med. 2016;14:273.CrossRefPubMedPubMedCentral Galon J, Fox BA, Bifulco CB, Masucci G, Rau T, Botti G, et al. Immunoscore and Immunoprofiling in cancer: an update from the melanoma and immunotherapy bridge 2015. J Transl Med. 2016;14:273.CrossRefPubMedPubMedCentral
11.
Zurück zum Zitat Kirilovsky A, Marliot F, El Sissy C, Haicheur N, Galon J, Pages F. Rational bases for the use of the Immunoscore in routine clinical settings as a prognostic and predictive biomarker in cancer patients. Int Immunol. 2016;28:373–82.CrossRefPubMedPubMedCentral Kirilovsky A, Marliot F, El Sissy C, Haicheur N, Galon J, Pages F. Rational bases for the use of the Immunoscore in routine clinical settings as a prognostic and predictive biomarker in cancer patients. Int Immunol. 2016;28:373–82.CrossRefPubMedPubMedCentral
12.
Zurück zum Zitat Rajnai H, Heyning FH, Koens L, Sebestyen A, Andrikovics H, Hogendoorn PC, et al. The density of CD8 + T-cell infiltration and expression of BCL2 predicts outcome of primary diffuse large B-cell lymphoma of bone. Virchows Arch. 2014;464:229–39.CrossRefPubMed Rajnai H, Heyning FH, Koens L, Sebestyen A, Andrikovics H, Hogendoorn PC, et al. The density of CD8 + T-cell infiltration and expression of BCL2 predicts outcome of primary diffuse large B-cell lymphoma of bone. Virchows Arch. 2014;464:229–39.CrossRefPubMed
13.
Zurück zum Zitat Coutinho R, Clear AJ, Mazzola E, Owen A, Greaves P, Wilson A, 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;100:363–9.CrossRefPubMedPubMedCentral Coutinho R, Clear AJ, Mazzola E, Owen A, Greaves P, Wilson A, 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;100:363–9.CrossRefPubMedPubMedCentral
14.
Zurück zum Zitat Gabrielson A, Wu Y, Wang H, Jiang J, Kallakury B, Gatalica Z, et al. Intratumoral CD3 and CD8 T-cell densities associated with relapse-free survival in HCC. Cancer Immunol Res. 2016;4:419 – 30.CrossRefPubMedPubMedCentral Gabrielson A, Wu Y, Wang H, Jiang J, Kallakury B, Gatalica Z, et al. Intratumoral CD3 and CD8 T-cell densities associated with relapse-free survival in HCC. Cancer Immunol Res. 2016;4:419 – 30.CrossRefPubMedPubMedCentral
15.
Zurück zum Zitat Horn H, Ziepert M, Becher C, Barth TF, Bernd HW, Feller AC, et al. MYC status in concert with BCL2 and BCL6 expression predicts outcome in diffuse large B-cell lymphoma. Blood. 2013;121:2253–63.CrossRefPubMed Horn H, Ziepert M, Becher C, Barth TF, Bernd HW, Feller AC, et al. MYC status in concert with BCL2 and BCL6 expression predicts outcome in diffuse large B-cell lymphoma. Blood. 2013;121:2253–63.CrossRefPubMed
16.
Zurück zum Zitat Schiefer AI, Kornauth C, Simonitsch-Klupp I, Skrabs C, Masel EK, Streubel B, et al. Impact of single or combined genomic alterations of TP53, MYC, and BCL2 on survival of patients with diffuse large B-cell lymphomas: a retrospective cohort study. Medicine (Baltimore). 2015;94:e2388.CrossRef Schiefer AI, Kornauth C, Simonitsch-Klupp I, Skrabs C, Masel EK, Streubel B, et al. Impact of single or combined genomic alterations of TP53, MYC, and BCL2 on survival of patients with diffuse large B-cell lymphomas: a retrospective cohort study. Medicine (Baltimore). 2015;94:e2388.CrossRef
17.
Zurück zum Zitat Scott DW, Gascoyne RD. The tumour microenvironment in B cell lymphomas. Nat Rev Cancer. 2014;14:517 – 34.CrossRefPubMed Scott DW, Gascoyne RD. The tumour microenvironment in B cell lymphomas. Nat Rev Cancer. 2014;14:517 – 34.CrossRefPubMed
18.
Zurück zum Zitat Yang ZZ, Novak AJ, Stenson MJ, Witzig TE, Ansell SM. Intratumoral CD4+ CD25+ regulatory T-cell-mediated suppression of infiltrating CD4+ T cells in B-cell non-Hodgkin lymphoma. Blood. 2006;107:3639–46.CrossRefPubMedPubMedCentral Yang ZZ, Novak AJ, Stenson MJ, Witzig TE, Ansell SM. Intratumoral CD4+ CD25+ regulatory T-cell-mediated suppression of infiltrating CD4+ T cells in B-cell non-Hodgkin lymphoma. Blood. 2006;107:3639–46.CrossRefPubMedPubMedCentral
19.
Zurück zum Zitat Yang ZZ, Novak AJ, Ziesmer SC, Witzig TE, Ansell SM. Attenuation of CD8(+) T-cell function by CD4(+)CD25(+) regulatory T cells in B-cell non-Hodgkin’s lymphoma. Cancer Res. 2006;66:10145–52.CrossRefPubMedPubMedCentral Yang ZZ, Novak AJ, Ziesmer SC, Witzig TE, Ansell SM. Attenuation of CD8(+) T-cell function by CD4(+)CD25(+) regulatory T cells in B-cell non-Hodgkin’s lymphoma. Cancer Res. 2006;66:10145–52.CrossRefPubMedPubMedCentral
20.
Zurück zum Zitat Galani IE, Wendel M, Stojanovic A, Jesiak M, Muller MM, Schellack C, et al. Regulatory T cells control macrophage accumulation and activation in lymphoma. Int J Cancer. 2010;127:1131–40.CrossRefPubMed Galani IE, Wendel M, Stojanovic A, Jesiak M, Muller MM, Schellack C, et al. Regulatory T cells control macrophage accumulation and activation in lymphoma. Int J Cancer. 2010;127:1131–40.CrossRefPubMed
21.
Zurück zum Zitat Xerri L, Huet S, Venstrom JM, Szafer-Glusman E, Fabiani B, Canioni D, et al. Rituximab treatment circumvents the prognostic impact of tumor-infiltrating T-cells in follicular lymphoma patients. Hum Pathol. 2017;64:128 – 36.CrossRefPubMed Xerri L, Huet S, Venstrom JM, Szafer-Glusman E, Fabiani B, Canioni D, et al. Rituximab treatment circumvents the prognostic impact of tumor-infiltrating T-cells in follicular lymphoma patients. Hum Pathol. 2017;64:128 – 36.CrossRefPubMed
22.
Zurück zum Zitat Fridman WH, Pages F, Sautes-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer. 2012;12:298–306.CrossRefPubMed Fridman WH, Pages F, Sautes-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer. 2012;12:298–306.CrossRefPubMed
23.
Zurück zum Zitat Kwon D, Kim S, Kim PJ, Go H, Nam SJ, Paik JH, et al. Clinicopathological analysis of programmed cell death 1 and programmed cell death ligand 1 expression in the tumour microenvironments of diffuse large B cell lymphomas. Histopathology. 2016;68:1079–89.CrossRefPubMed Kwon D, Kim S, Kim PJ, Go H, Nam SJ, Paik JH, et al. Clinicopathological analysis of programmed cell death 1 and programmed cell death ligand 1 expression in the tumour microenvironments of diffuse large B cell lymphomas. Histopathology. 2016;68:1079–89.CrossRefPubMed
24.
Zurück zum Zitat Li Z, Lai Y, Sun L, Zhang X, Liu R, Feng G, et al. PD-L1 expression is associated with massive lymphocyte infiltration and histology in gastric cancer. Hum Pathol. 2016;55:182–9.CrossRefPubMed Li Z, Lai Y, Sun L, Zhang X, Liu R, Feng G, et al. PD-L1 expression is associated with massive lymphocyte infiltration and histology in gastric cancer. Hum Pathol. 2016;55:182–9.CrossRefPubMed
25.
Zurück zum Zitat Iacovelli R, Nole F, Verri E, Renne G, Paglino C, Santoni M, et al. Prognostic role of PD-L1 expression in renal cell carcinoma. A systematic review and meta-analysis. Target Oncol. 2016;11:143–8.CrossRefPubMed Iacovelli R, Nole F, Verri E, Renne G, Paglino C, Santoni M, et al. Prognostic role of PD-L1 expression in renal cell carcinoma. A systematic review and meta-analysis. Target Oncol. 2016;11:143–8.CrossRefPubMed
27.
Zurück zum Zitat Ishii H, Azuma K, Kawahara A, Yamada K, Imamura Y, Tokito T, et al. Significance of programmed cell death-ligand 1 expression and its association with survival in patients with small cell lung cancer. J Thorac Oncol. 2015;10:426 – 30.CrossRefPubMed Ishii H, Azuma K, Kawahara A, Yamada K, Imamura Y, Tokito T, et al. Significance of programmed cell death-ligand 1 expression and its association with survival in patients with small cell lung cancer. J Thorac Oncol. 2015;10:426 – 30.CrossRefPubMed
28.
Zurück zum Zitat Webb JR, Milne K, Kroeger DR, Nelson BH. PD-L1 expression is associated with tumor-infiltrating T cells and favorable prognosis in high-grade serous ovarian cancer. Gynecol Oncol. 2016;141:293–302. Webb JR, Milne K, Kroeger DR, Nelson BH. PD-L1 expression is associated with tumor-infiltrating T cells and favorable prognosis in high-grade serous ovarian cancer. Gynecol Oncol. 2016;141:293–302.
29.
Zurück zum Zitat Gadiot J, Hooijkaas AI, Kaiser AD, van Tinteren H, van Boven H, Blank C. Overall survival and PD-L1 expression in metastasized malignant melanoma. Cancer. 2011;117:2192 – 201.CrossRefPubMed Gadiot J, Hooijkaas AI, Kaiser AD, van Tinteren H, van Boven H, Blank C. Overall survival and PD-L1 expression in metastasized malignant melanoma. Cancer. 2011;117:2192 – 201.CrossRefPubMed
30.
Zurück zum Zitat Wang A, Wang HY, Liu Y, Zhao MC, Zhang HJ, Lu ZY, et al. The prognostic value of PD-L1 expression for non-small cell lung cancer patients: a meta-analysis. Eur J Surg Oncol. 2015;41:450–6.CrossRefPubMed Wang A, Wang HY, Liu Y, Zhao MC, Zhang HJ, Lu ZY, et al. The prognostic value of PD-L1 expression for non-small cell lung cancer patients: a meta-analysis. Eur J Surg Oncol. 2015;41:450–6.CrossRefPubMed
31.
Zurück zum Zitat Velcheti V, Schalper KA, Carvajal DE, Anagnostou VK, Syrigos KN, Sznol M, et al. Programmed death ligand-1 expression in non-small cell lung cancer. Lab Investig. 2014;94:107 – 16.CrossRefPubMed Velcheti V, Schalper KA, Carvajal DE, Anagnostou VK, Syrigos KN, Sznol M, et al. Programmed death ligand-1 expression in non-small cell lung cancer. Lab Investig. 2014;94:107 – 16.CrossRefPubMed
32.
Zurück zum Zitat Jo JC, Kim M, Choi Y, Kim HJ, Kim JE, Chae SW, et al. Expression of programmed cell death 1 and programmed cell death ligand 1 in extranodal NK/T-cell lymphoma, nasal type. Ann Hematol. 2017;96:25–31.CrossRefPubMed Jo JC, Kim M, Choi Y, Kim HJ, Kim JE, Chae SW, et al. Expression of programmed cell death 1 and programmed cell death ligand 1 in extranodal NK/T-cell lymphoma, nasal type. Ann Hematol. 2017;96:25–31.CrossRefPubMed
33.
Zurück zum Zitat Hirsch FR, McElhinny A, Stanforth D, Ranger-Moore J, Jansson M, Kulangara K, et al. PD-L1 immunohistochemistry assays for lung cancer: results from phase 1 of the blueprint PD-L1 IHC assay comparison project. J Thoracic Oncol. 2017;12:208–22.CrossRef Hirsch FR, McElhinny A, Stanforth D, Ranger-Moore J, Jansson M, Kulangara K, et al. PD-L1 immunohistochemistry assays for lung cancer: results from phase 1 of the blueprint PD-L1 IHC assay comparison project. J Thoracic Oncol. 2017;12:208–22.CrossRef
34.
Zurück zum Zitat Gaule P, Smithy JW, Toki M, et al. A Quantitative Comparison of Antibodies to Programmed Cell Death 1 Ligand 1. JAMA Oncol. 2017;3:256–9.CrossRef Gaule P, Smithy JW, Toki M, et al. A Quantitative Comparison of Antibodies to Programmed Cell Death 1 Ligand 1. JAMA Oncol. 2017;3:256–9.CrossRef
35.
Zurück zum Zitat Rimm DL, Han G, Taube JM, et al. A Prospective, Multi-institutional, Pathologist-Based Assessment of 4 Immunohistochemistry Assays for PD-L1 Expression in Non-Small Cell Lung Cancer. JAMA Oncol. 2017;3:1051–8.CrossRefPubMedPubMedCentral Rimm DL, Han G, Taube JM, et al. A Prospective, Multi-institutional, Pathologist-Based Assessment of 4 Immunohistochemistry Assays for PD-L1 Expression in Non-Small Cell Lung Cancer. JAMA Oncol. 2017;3:1051–8.CrossRefPubMedPubMedCentral
36.
Zurück zum Zitat Held G, Poschel V, Pfreundschuh M. Rituximab for the treatment of diffuse large B-cell lymphomas. Expert Rev Anticancer Ther. 2006;6:1175–86.CrossRefPubMed Held G, Poschel V, Pfreundschuh M. Rituximab for the treatment of diffuse large B-cell lymphomas. Expert Rev Anticancer Ther. 2006;6:1175–86.CrossRefPubMed
Metadaten
Titel
CD3+/CD8+ T-cell density and tumoral PD-L1 predict survival irrespective of rituximab treatment in Chinese diffuse large B-cell lymphoma patients
verfasst von
Yunfei Shi
Lijuan Deng
Yuqin Song
Dongmei Lin
Yumei Lai
LiXin Zhou
Lei Yang
Xianghong Li
Publikationsdatum
10.05.2018
Verlag
Springer Japan
Erschienen in
International Journal of Hematology / Ausgabe 3/2018
Print ISSN: 0925-5710
Elektronische ISSN: 1865-3774
DOI
https://doi.org/10.1007/s12185-018-2466-7

Weitere Artikel der Ausgabe 3/2018

International Journal of Hematology 3/2018 Zur Ausgabe

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.