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© 2002 American Society for Clinical Oncology
T Helper Cell Activation in B-Cell LymphomasUniversity Hospital, Zurich, Switzerland To the Editor:In an excellent article, published in the February 1, 2001, issue of the Journal of Clinical Oncology, Ansell et al1 reported that high numbers of tumor-infiltrating CD4+ T cells in pretreatment biopsies of large B-cell lymphomas are associated with prolonged relapse-free survival. These data suggest that high CD4+ T-cell counts in involved tissue of large B-cell lymphomas are indeed indicative of effective antitumor immune responses. The recent discovery that a significant proportion of non-Hodgkin’s lymphomas, including half of all large B-cell lymphomas, contain DNA sequences derived from the oncogenic simian virus 402,3 further supports the view that CD4+ T cells are critically involved in immune surveillance of B-cell lymphoma tumor cells, especially in light of previous reports which clearly demonstrated that CD4+ T-cell help is required for the eradication of simian virus 40–induced experimental tumors by CD8+ T cells.4 The most common B-cell malignancies in Europe and the United States are classic Hodgkin’s disease (HD), follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLCL).5 Although all of these lymphomas seem to derive from germinal center B cells,6 their natural histories are very different. Untreated HD, for example, takes a brief course with an average life expectancy of 1 or 2 years. FL, an indolent non-Hodgkin’s lymphoma, is characterized by a long median survival, even without therapy, and spontaneous remissions, although rare, are possible. DLCL, on the other hand, is an aggressive B-cell neoplasm and median survival is measured in months. An important question arises at this juncture. Do the numbers or activation states of tumor-infiltrating CD4+ T cells reflect the grade of malignancy among different B-cell lymphomas? To address this problem, cell suspensions isolated from diagnostic lymph node biopsies were double-stained with fluorescein isothiocyanate–conjugated mouse monoclonal antibodies to human CD4 and phycoerythrin-conjugated mouse monoclonal antibodies to the human early activation antigen, CD697 (DAKO, Glostrup, Denmark). In parallel, samples were labelled with matching fluorescein isothiocyanate– and phycoerythrin-conjugated isotype control antibodies (DAKO) to determine unspecific staining. To quantify cell surface expression of CD4 and CD69, respectively, samples were analyzed by flow cytometry and mean fluorescence intensities were determined. As shown in Fig. 1A, the numbers of CD4+ T cells in benign, reactive lymph nodes were comparable with those measured in HD-involved tissue. The tumor cell–rich FL and DLCL samples contained fewer CD4+ T cells. A different picture emerged when the numbers of early activated, CD69-expressing, CD4+ T cells were compared. Unlike reactive lymph node control samples, the three B-cell neoplasms showed significant activation of tumor-associated CD4+ T cells (Fig. 1B). However, there was no difference in CD69 expression among different B-cell lymphomas. From these data, it can be concluded that the number of infiltrating CD4+ T cells is independent of the grade of malignancy. Although early activation of CD4+ T cells seems to describe a characteristic feature of B-cell neoplasms, this activation does not correlate with tumor aggressiveness.
The idea that effective immune surveillance in B-cell lymphomas largely depends on the number of surveying cells, eg, tumor-infiltrating CD4+ cells, seems to be confirmed by the results reported by Ansell et al,1 at least in cases of DLCL. The data presented here, on the other hand, argue against a generalization of this quantitative concept of tumor growth control. Whereas low-grade FL tumor cells still depend on antigen and a germinal center microenvironment,6 the more aggressive DLCL tumor cells are independent of these growth restrictions, yet, as shown in Fig. 1B, both diseases present with similar numbers of activated CD4+ T cells. Sequence analysis of rearranged variable-region immunoglobulin genes has shown that the same tumor precursor B-cell can develop into very different types of B-cell lymphoma.8 The identification of molecular changes in the malignant progenies of germinal center B cells will help us develop a clearer picture of the complex interactions between B-cell lymphomas and the immune system. REFERENCES
1.
Ansell SM, Stenson M, Habermann TM, et al: CD4+ T-cell immune response to large B-cell non-Hodgkin’s lymphoma predicts patient outcome. J Clin Oncol 19: 720-726, 2001 2. Vilchez RA, Madden CR, Kozinetz CA, et al: Association between simian virus 40 and non-Hodgkin lymphoma. Lancet 359: 817-823, 2002[CrossRef][Medline] 3. Shivapurkar N, Harada K, Reddy J, et al: Presence of simian virus 40 DNA sequences in human lymphomas. Lancet 359: 851-852, 2002[CrossRef][Medline]
4.
Utermohlen O, Schulze-Garg C, Warnecke RG, et al: Simian virus 40 large-T-antigen-specific rejection of mKSA tumor cells in BALB/c mice is critically dependent on both strictly tumor-associated, tumor-specific CD8+ cytotoxic T lymphocytes and CD4+ T helper cells. J Virol 75: 10593-10602, 2002 5. Harris NL: Principles of the revised European-American Lymphoma Classification (from the International Lymphoma Study Group). Ann Oncol 8: 11-16, 1997
6.
Kuppers R, Klein U, Hansmann ML, et al: Cellular origin of human B-cell lymphomas. N Engl J Med 341: 1520-1529, 1999
7.
Hara T, Jung LK, Bjorndahl JM, et al: Human T cell activation: III. Rapid induction of a phosphorylated 28kD/32kD disulfide-linked early activation antigen (EA1) by 12-o-tetradecanoyl phorbol-13-acetate, mitogens, and antigens. J Exp Med 164: 1988-2005, 1986
8.
Brauninger A, Hansmann ML, Strickler JG, et al: Identification of common germinal-center B-cell precursors in two patients with both Hodgkin’s disease and non-Hodgkin’s lymphoma. N Engl J Med 340: 1239-1247, 1999
ResponseMayo Clinic, Rochester, MN In Reply:We read with interest the correspondence from Dr H. Bosshart describing a significant difference in the percentage of CD4+ T cells in follicular lymphoma and diffuse large-cell lymphoma when compared with reactive lymph nodes and Hodgkin’s lymphoma. We also noted the significantly higher percentage of CD69+ T-helper cells found in the various B-cell lymphoma specimens when compared with the reactive nodes and that the percentage of CD69+ T cells in the various types of B-cell malignancies was similar. We agree that CD69+ CD4+ cells are a feature of the T-helper cells in B-cell malignancies and have also found that the majority of CD4+ T cells in B-cell lymphomas are CD69+. Although we have also consistently found the percentage of CD69+ T cells in B-cell lymphomas to be approximately 40% to 70%, we have found that the absolute numbers of these T cells may vary greatly. Therefore, although we agree that a generalization of the quantitative concept of numbers of infiltrating CD4+ T-cells to other B-cell malignancies such as Hodgkin’s lymphoma (where T cells may play a different role) may not be appropriate, we do feel that the number of infiltrating CD4+ T cells in both large-cell and follicular lymphoma has significance. We have previously shown that increased CD4+ cells in follicular lymphoma predicts patient outcome1 and Xu et al2 have confirmed our observation that the number of tumor infiltrating CD4+ T cells has prognostic significance in large-cell lymphoma. What is unknown, however, is whether the increased number of infiltrating cells is truly indicative of effective immune surveillance. As stated by Dr Bosshart, the interaction between the immune system, particularly CD4+ T cells, and the malignant clone is very complex. In our experience, it has been difficult to determine whether the increased numbers of CD4+ T cells present in lymphoma tissue is indicative of an antitumor immune response or just a nonspecific representation of the patient’s overall immune status. We have investigated the phenotype of infiltrating CD4+ T cells but have not been able to identify a predominant CD4+ T-cell subset in areas of B-cell lymphoma. Using flow cytometry, we have assessed the percentage and number of CD4+ T cells in lymphoma specimens that express gamma interferon, interleukin-4, CXCR5, or CD25, to specifically evaluate the presence of Th1, Th2, TFH cells (Th cells with B-cell helper function)3 and regulatory T cells.4 In 30 lymphoma specimens with various indolent and aggressive histologies, the median number of Th1, Th2, TFH, and regulatory T cells expressed as a percent of the total CD4+ cells was 12.5% (range, 1% to 51%), 2.5% (range, 0.7% to 5.9%), 10.3% (range, 2.5% to 42.7%), and 4.4% (range, 2.1% to 14.6%), respectively. In 10 of these patients, we also evaluated the T-cell receptor repertoire of the CD4+ cells using T-cell spectratyping and found that the T-cell repertoire was normally diverse in all patients. These studies would suggest that the activated T cells present in lymphoma specimens are more likely to represent a nonspecific infiltration of immune cells rather than a specific antitumor clonal expansion, but further studies to evaluate the nature of infiltrating CD4+ T cells and to increase their tumor-specific activity are clearly needed. REFERENCES 1. Ansell SM, Stenson M, Kurtin PJ, et al: Infiltration by activated CD4+ T-cells is an important determinant of prognosis in low grade and intermediate grade B-cell lymphomas. Proc Am Soc Clin Oncol 18: 15, 1999 (abstr 15) 2. Xu Y, Kroft SH, McKenna RW, et al: Prognostic significance of tumour-infiltrating T lymphocytes and T-cell subsets in de novo diffuse large B-cell lymphoma: A multiparameter flow cytometry study. Br J Haematol 112: 945-949, 2001[CrossRef][Medline]
3.
Breitfeld D, Ohl L, Kremmer E, et al: Follicular B helper T cells express CXC chemokine receptor 5, localize to B cell follicles, and support immunoglobulin production. J Exp Med 192: 1545-1552, 2000 4. Sakaguchi S, Sakaguchi N, Shimizu J, et al: Immunologic tolerance maintained by CD25+ CD4+ regulatory T cells: Their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance. Immunol Rev 182: 18-32, 2001[CrossRef][Medline]
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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