Interleukin-12 Overcomes Paclitaxel-Mediated Suppression of T-Cell Proliferation

Abstract

The antineoplastic agent paclitaxel (TAXOL) is a potent inhibitor of tumor cell division and a useful chemotherapeutic for the treatment of refractory ovarian and breast carcinoma. Multiple immune system actions have been ascribed to paclitaxel, including the capacity to induce macrophage antitumor cytotoxic molecule production. However, T-cells are susceptible to paclitaxel's cytostatic functions, and no studies have investigated the effects of direct paclitaxel administration on lymphocyte function in the tumor-bearing host (TBH). Because paclitaxel is currently used as an antitumor chemotherapeutic agent and tumor growth alters leukocyte functions, we assessed T-cell function following chemotherapeutic-type paclitaxel treatment. Paclitaxel administration significantly compromised the proliferative capacity of both normal host and TBH lymphocytes in vitro. Although tumor growth impaired T-cell interferon-gamma (IFN-gamma) production, paclitaxel treatment did not alter IFN-gamma. We speculate that the immunostimulatory cytokine interleukin-12 (IL-12), which promoted T-cell activation and proliferation, was capable of reversing paclitaxel-mediated immunosuppression. Exogenous IL-12 fully reconstituted proliferative reactivity and enhanced IFN-gamma production by both normal host and TBH lymphocytes in vitro. Collectively, these data suggest that chemotherapeutic paclitaxel regimens impart significant but reversible inhibition of lymphocyte populations, and IL-12 may be a useful ancillary immunotherapeutic to overcome paclitaxel-induced modulation of lymphocyte activities.

Validation of Intratumoral T-bet+ Lymphoid Cells as Predictors of Disease-Free Survival in Breast Cancer

“…Evidence also suggests that taxanes could exert an immunostimulatory effect against breast cancer (63)(64)(65)(66) by inducing a Th1 response. Paclitaxel has been shown to stimulate the secretion by macrophages of proinflammatory and Th1 cytokines such as IL1b or IL12 (67,68). Carson and colleagues (65) showed that in 227 breast cancer patients, T-cell activation was significantly higher in patients receiving taxanes compared with non-taxane-containing regimens.…”

Cellular Immunity in Breast Cancer Patients Completing Taxane Treatment

“…Stimulation of macrophages with paclitaxel leads to the induction of important pathways involved in the elimination of microbes (e.g., inducible nitric oxide synthesis) as well as the production of proinflammatory cytokines such as interleukin (IL)-1␤, tumor necrosis factor ␣, and IL-8 (5). Furthermore, paclitaxel-induced production of IL-12 by tumor-associated macrophages may be important in alleviating the T-cell suppression that is observed in the tumor-bearing host (6). In vitro studies of the direct effects of paclitaxel on the cytotoxic activity of T cells and natural killer (NK) cells have generally revealed an inhibitory effect, but some studies suggest a more complex effect of taxanes on the function of these lymphocyte populations in vivo.…”

Immune changes in patients with advanced breast cancer undergoing chemotherapy with taxanes

“…Paclitaxel induces IL-8 and this probably may have a positive role in controlling tumour growth (Lee et al, 2000a). Paclitaxel restores IL-12 production in the tumour bearing host and a novel immunotherapeutic component to the pleiotropic activities of NO is ascribed (Mullins et al, 1998). IL-2, IL-12, and gamma-IFN (IFN-g) levels were not detecable, during the administration of taxanes (Mullins et al, 1998;Lee et al, 2000b).…”

“…Paclitaxel restores IL-12 production in the tumour bearing host and a novel immunotherapeutic component to the pleiotropic activities of NO is ascribed (Mullins et al, 1998). IL-2, IL-12, and gamma-IFN (IFN-g) levels were not detecable, during the administration of taxanes (Mullins et al, 1998;Lee et al, 2000b). NK cytotoxic activity decreased in docetaxel-treated patient (Lee et al, 2000b).…”