Prognostic impact of tumour‐infiltrating Th2 and regulatory T cells in classical Hodgkin lymphoma

Classical Hodgkin Lymphoma (cHL) is morphologically characterized by a small number of tumour cells, Hodgkin and Reed–Sternberg (HRS) cells, surrounded by numerous tumour‐infiltrating lymphocytes (TIL). The functional role of these TIL is still controversial. While generally considered to represent an anti‐tumour immune response, TIL in cHL might result from the profoundly deregulated immunity of cHL patients. Eighty‐seven cases of cHL were available to evaluate the prognostical significance of tumour‐infiltrating cytotoxic T lymphocytes (CTL), T helper 1 (Th1) cells, T helper 2 (Th2) cells and regulatory T cells (Treg). We confirm that in cHL the microenvironment is dominated by Th2 cells and Treg and show that large numbers of Th2 cells are associated with significantly improved disease‐free survival (p = 0.021) and event‐free survival (p = 0.012). Furthermore, a high ratio of Treg over Th2 cells resulted in a significantly shortened disease‐free survival (p = 0.025). These observations suggest that Treg may exert inhibitory effects on anti‐tumour immune responses mediated through Th2 cells and that Th2 cells may be more important for effective anti‐tumour immunity than anticipated. Copyright © 2008 John Wiley & Sons, Ltd.

[1]  Stefano A Pileri,et al.  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 , 2008, Haematologica.

[2]  Tomoki Ito,et al.  Hodgkin's Reed‐Sternberg cell line (KM‐H2) promotes a bidirectional differentiation of CD4+CD25+Foxp3+ T cells and CD4+ cytotoxic T lymphocytes from CD4+ naive T cells , 2007, Journal of leukocyte biology.

[3]  Emili Montserrat,et al.  High numbers of tumor-infiltrating FOXP3-positive regulatory T cells are associated with improved overall survival in follicular lymphoma. , 2006, Blood.

[4]  yang-xin fu,et al.  Tumor-infiltrating T lymphocytes: friends or foes? , 2006, Laboratory Investigation.

[5]  Gerd Ritter,et al.  Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[6]  A. Banham,et al.  Cutting Edge: Direct Suppression of B Cells by CD4+CD25+ Regulatory T Cells1 , 2005, The Journal of Immunology.

[7]  S. Sakaguchi Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self , 2005, Nature Immunology.

[8]  Giovanna Roncador,et al.  Outcome in Hodgkin's Lymphoma Can Be Predicted from the Presence of Accompanying Cytotoxic and Regulatory T Cells , 2005, Clinical Cancer Research.

[9]  M. Büchler,et al.  Control of T-cell-mediated immune response by HLA class I in human pancreatic carcinoma. , 2005, Clinical cancer research : an official journal of the American Association for Cancer Research.

[10]  A. van den Berg,et al.  Expression of the T-cell transcription factors, GATA-3 and T-bet, in the neoplastic cells of Hodgkin lymphomas. , 2005, The American journal of pathology.

[11]  George Coukos,et al.  Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival , 2004, Nature Medicine.

[12]  C. Ostwald,et al.  Prognostic role of CD8+ tumor-infiltrating lymphocytes in stage III colorectal cancer with and without microsatellite instability. , 2004, Human pathology.

[13]  Douglas G Altman,et al.  The logrank test , 2004, BMJ : British Medical Journal.

[14]  R. Barker,et al.  Immunosuppressive regulatory T cells are abundant in the reactive lymphocytes of Hodgkin lymphoma. , 2004, Blood.

[15]  J. Delfraissy,et al.  In human B cells, IL-12 triggers a cascade of molecular events similar to Th1 commitment. , 2003, Blood.

[16]  C. Meijer,et al.  High numbers of granzyme B/CD8‐positive tumour‐infiltrating lymphocytes in nasopharyngeal carcinoma biopsies predict rapid fatal outcome in patients treated with curative intent , 2002, The Journal of pathology.

[17]  Tak H. Lee,et al.  Cytokine Coexpression During Human Th1/Th2 Cell Differentiation: Direct Evidence for Coordinated Expression of Th2 Cytokines1 , 2002, The Journal of Immunology.

[18]  S. Szabo,et al.  T-bet regulates IgG class switching and pathogenic autoantibody production , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[19]  G. Niedobitek,et al.  Epstein‐Barr virus infection and human malignancies , 2001 .

[20]  G. Niedobitek,et al.  Epstein-Barr virus infection and human malignancies. , 2001, International journal of experimental pathology.

[21]  Alberto Mantovani,et al.  Inflammation and cancer: back to Virchow? , 2001, The Lancet.

[22]  A. van den Berg,et al.  Interaction between host T cells and Reed-Sternberg cells in Hodgkin lymphomas. , 2000, Seminars in cancer biology.

[23]  Laurie H Glimcher,et al.  A Novel Transcription Factor, T-bet, Directs Th1 Lineage Commitment , 2000, Cell.

[24]  K. Rajewsky,et al.  Cellular origin of human B-cell lymphomas. , 1999, The New England journal of medicine.

[25]  A. van den Berg,et al.  Immune reactions in classical Hodgkin's lymphoma. , 1999, Seminars in hematology.

[26]  C. Lowenstein,et al.  The Central Role of CD4+ T Cells in the Antitumor Immune Response , 1998, The Journal of experimental medicine.

[27]  L. Glimcher,et al.  c-maf Promotes T Helper Cell Type 2 (Th2) and Attenuates Th1 Differentiation by Both Interleukin 4–dependent and –independent Mechanisms , 1998, The Journal of experimental medicine.

[28]  P. V. van Diest,et al.  Activated cytotoxic T cells as prognostic marker in Hodgkin's disease. , 1997, Blood.

[29]  Laurie H Glimcher,et al.  The Proto-Oncogene c-maf Is Responsible for Tissue-Specific Expression of Interleukin-4 , 1996, Cell.

[30]  E. Kaplan,et al.  Nonparametric Estimation from Incomplete Observations , 1958 .