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

Abstract

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 ¼ 0.021) and event-free survival ( p ¼ 0.012). Furthermore, a high ratio of Treg over Th2 cells resulted in a significantly shortened disease-free survival ( p ¼ 0.025). These observations suggest that Treg may exert inhibitory effects on antitumour immune responses mediated through Th2 cells and that Th2 cells may be more important for effective anti-tumour immunity than anticipated.

Expression of cancer testis antigen CT45 in classical Hodgkin lymphoma and other B-cell lymphomas

“…Given the >50% frequency of CT45 antigen expression in these patients, this finding indicates that either CT45 is of low immunogenicity or that the anti-CT45 immune responses in these patients have been suppressed. It is well documented that tumor-infiltrating lymphocytes (TILs) in cHL, distinctive from anti-tumor TILs found in solid tumors such as melanoma, are dominated by Th2 cells and FOXP3-positive regulatory T (Treg) cells (9,23,24), whereas cytotoxic T cells are underrepresented. Moreover, it was shown recently that the nature of the TILs in cHL is of prognostic significance, and patients with a high ratio of Treg cells to Th2 cells would have a significantly shortened disease-free survival (24).…”

“…It is well documented that tumor-infiltrating lymphocytes (TILs) in cHL, distinctive from anti-tumor TILs found in solid tumors such as melanoma, are dominated by Th2 cells and FOXP3-positive regulatory T (Treg) cells (9,23,24), whereas cytotoxic T cells are underrepresented. Moreover, it was shown recently that the nature of the TILs in cHL is of prognostic significance, and patients with a high ratio of Treg cells to Th2 cells would have a significantly shortened disease-free survival (24). This finding, in conjunction with our failure to identify any antibody response to MAGE-A, NY-ESO-1, and p53 in these patients, led us to believe that specific antitumor responses are profoundly suppressed in cHL patients as a result of the Treg-rich microenvironment, and this suppression would explain the lack of anti-CT45 response in the presence of abundant CT45 antigen expression.…”

Tumor-Released Survivin Induces a Type-2 T Cell Response and Decreases Cytotoxic T Cell Function, in Vitro

“…Type 1 responses are typically decreased with a concomitant increase in type 2 cell numbers and cytokine levels [13][14][15][16][17][18][19][20][21][22]. The potential for metastasis and angiogenesis is increased by the presence of IL-4 and IL-6, respectively, and the type 2 polarization increases both of these cytokines [6,23].…”

On the prediction of Hodgkin lymphoma treatment response

“…The adverse prognostic factors identified were: male older than 45, stage IV disease, hemoglobin lower than 10.5 g/dl, lymphocyte count lower than 600 /µl (or less than 8%), albumin lower than 4.0 g/dl, and white blood count greater than 15,000 /µl [2,3]. Other studies also took into account mixed-cellularity or lymphocyte-depleted histologies, the presence of B symptoms or high erythrocyte sedimentation rate, and bulky disease as adverse prognostic factors [4,5].…”