Activated cytotoxic T cells as prognostic marker in Hodgkin's disease

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.