Activated Cytotoxic T Cells as Prognostic Marker in Hodgkin's Disease

Abstract

Although the results of treatment of Hodgkin's disease (HD) have improved considerably in the last decades, the disease remains fatal in a minority of patients. We have recently shown that numbers of activated cytotoxic T cells (CTLs), present in tumor biopsy specimens, differ considerably among individual HD patients. Because CTLs are the major effector cells in elimination of neoplastic cells, we investigated whether the number of activated CTLs is related to the clinical outcome of the individual patient with HD. Activated CTLs present in tumor biopsy specimens of patients with nodular sclerosis or mixed cellularity HD were identified by immunohistochemistry using an antibody directed against granzyme B (GrB), a major constituent of the cytotoxic granules of activated CTLs and natural killer cells, and an antibody directed against CD8. The presence of a high percentage of GrB+ lymphocytes was found to be an unfavorable prognostic marker. The large majority of GrB+ cells were also CD8+, indicating that these cells are activated CTLs. Prognosis was found to decrease with increasing percentages of GrB+ lymphocytes. Optimal discrimination between patients with good and poor prognosis was obtained when the threshold was set at 15% GrB+ cells; 6 of 10 patients with ≥15% GrB+ lymphocytes died as a result of the disease, as compared with 6 of 70 patients with less than 15% GrB+ lymphocytes (P < .0001). In stage-2 patients, the percentage of GrB+ lymphocytes retained its predictive value in a multivariate analysis including histology, sex, age, erythrocyte sedimentation rate, and the presence of B symptoms as covariables. In addition, patients with ≥15% GrB+ lymphocytes had a shortened progression-free survival time (P = .002). We conclude that a high percentage of activated CTLs present in biopsy material of HD patients is a strong indicator for an unfavorable clinical outcome.

Flow cytometry for assessment of the tumor microenvironment in pediatric Hodgkin lymphoma

“…A recent study of adults with HL found a correlation between CD8-positive lymphocyte proportions and freedom from treatment failure, 29 although previous studies were contrasting. 30 We noted that children with MC subtype, whose tumor samples had higher percentages of CD8-positive T cells, had a better CCR rate, although CD8-positive lymphocyte proportion itself was not associated with outcome in this study. However, we did observe that patients whose tumors had a higher percentage of activated HLA-DR/CD38 copositive lymphocytes had higher CCR rates, indicating that this proportion may predict relapse or refractoriness.…”

Epstein–Barr virus presence in pediatric diffuse large B‐cell lymphoma reveals a particular association and latency patterns: Analysis of viral role in tumor microenvironment

“…We have not found a relationship between EBV presence and CD4 þ or Foxp3 þ cell number in pediatric DLBCL, confirming the lack of correlation between viral presence and different subtypes of T cell. On the other hand, although an increased number of CTLs has been linked to EBV expression in HL, 50 there was no relationship between CD3 þ and CD8 þ cells with EBV presence in our pediatric DLBCL series (Table 3).…”

Immunohistochemical detection of cytotoxic lymphocytes in malignant serous effusions

“…18,19 Antibodies to TIA-1, as well as other cytolytic granule effector proteins, such as perforin and granzyme B, have been shown to be useful for evaluating the cytotoxic response of CTLs and NK cells to allografts, viral infection, autoimmune diseases, and tumors. [20][21][22][23][24][25] The antibody to TIA-1 works extremely well in formalin-, Bouin-, and B5-fixed tissue for the specific immunohistochemical detection of CTLs and NK cells. 18,19,26 In this study, the number of CTLs and NK cells, as estimated by the percentage of TIA-1-positive lymphocytes, showed a significant correlation with the presence of malignancy, whereas no correlation was found using pan T-cell markers.…”