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Reply to the Letter to the Editor from Oudejans et al

National Cheng Kung University, Tainan, Taiwan

Dan Jones

The University of Texas M.D. Anderson Cancer Center, Houston, Texas

In Response:

We appreciate the comments in the letter by Oudejans et al. about whether the presence of CTLs is a favorable or unfavorable factor for prognosis in diffuse large B-cell lymphoma (1, 2). Whereas the studies by their group (2, 3) and others (4) find that a high percentage of CTLs are associated with poor outcome, there are also other studies besides our own showing that high numbers of CD8⁺ T cells in diffuse large B-cell lymphoma may be associated instead with superior survival (5, 6). The tissue site distribution of diffuse large B-cell lymphoma in each study is likely one explanation of the different results. For example, 46% of cases in our study were extranodal, and there was a trend toward different patterns of T-cell distribution (and tumor prognosis) in those cases compared with the nodal tumors.

However, we agree that the study methodologies can also affect the result, including particular immunostaining protocols, antibodies used, method of quantitation, and selection of analyzed areas. In our study, we counted the absolute granzyme B⁺ cells in areas of most dense intratumoral infiltration, expressed as cell number per high-power field. In contrast, Oudejans' group randomly selected tumor areas using an automatic scanning stage and expressed the granzyme B⁺ cells as the percentage of granzyme B⁺ cells divided by the total CD3⁺ cells. These different methods can yield different results even in the same study. For example, in the article by Riemersma et al. (3), the absolute number of granzyme B⁺ cells in diffuse large B-cell lymphoma of the central nervous system/brain was lower than that in skin and nodal tumors, but the percentage of CTLs (number of granzyme B⁺ cells / number of CD3⁺ cells) showed the reverse result.

We would also emphasize that the interaction between the immune system and diffuse large B-cell lymphoma is complex, with differential T-cell and dendritic cell responses. In our study, we hypothesized that the cooperative action of infiltrating dendritic cells and CTLs in a subset of diffuse large B-cell lymphoma may contribute to a favorable prognosis by boosting dendritic cell–associated T-cell immunity. Whether this immunotherapy strategy can be used to boost responses in diffuse large B-cell lymphoma remains to be determined empirically. In view of the current progress, however, it may be clinically feasible in the near future (7).

References

1. Chang KC, Huang GC, Jones D, Lin YH. Distribution patterns of dendritic cells and T cells in diffuse large B-cell lymphomas correlate with prognoses. Clin Cancer Res 2007;13:6666–72.[Abstract/Free Full Text]
2. Muris JJ, Meijer CJ, Cillessen SA, et al. Prognostic significance of activated cytotoxic T-lymphocytes in primary nodal diffuse large B-cell lymphomas. Leukemia 2004;18:589–96.[CrossRef][Medline]
3. Riemersma SA, Oudejans JJ, Vonk MJ, et al. High numbers of tumour-infiltrating activated cytotoxic T lymphocytes, and frequent loss of HLA class I and II expression, are features of aggressive B cell lymphomas of the brain and testis. J Pathol 2005;206:328–36.[CrossRef][Medline]
4. Hasselblom S, Sigurdadottir M, Hansson U, Nilsson-Ehle H, Ridell B, Andersson PO. The number of tumour-infiltrating TIA-1+ cytotoxic T cells but not FOXP3+ regulatory T cells predicts outcome in diffuse large B-cell lymphoma. Br J Haematol 2007;137:364–73.[CrossRef][Medline]
5. Lippman SM, Spier CM, Miller TP, Slymen DJ, Rybski JA, Grogan TM. Tumor-infiltrating T-lymphocytes in B-cell diffuse large cell lymphoma related to disease course. Mod Pathol 1990;3:361–7.[Medline]
6. Rimsza LM, Roberts RA, Miller TP, et al. Loss of MHC class II gene and protein expression in diffuse large B-cell lymphoma is related to decreased tumor immunosurveillance and poor patient survival regardless of other prognostic factors: a follow-up study from the Leukemia and Lymphoma Molecular Profiling Project. Blood 2004;103:4251–8.[Abstract/Free Full Text]
7. Wang J, Press OW, Lindgren CG, et al. Cellular immunotherapy for follicular lymphoma using genetically modified CD20-specific CD8+ cytotoxic T lymphocytes. Mol Ther 2004;9:577–86.[CrossRef][Medline]

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