Paclitaxel-induced macrophage activities in the tumor-bearing host: immunologic implications and therapeutic applications
Mullins, David Warren
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Tumors induce immune dysfunction through the production of soluble factors that subvert macrophage (Mf) function to favor tumor growth. Previous studies suggested that tumor-induced immune cell dysfunction may be reversible through regimens that disrupt tumor cell suppressor mechanisms and concurrently promote tumoricidal activities. Because the antineoplastic agent paclitaxel (TAXOL) activates Mf function, we studied mechanisms of paclitaxel-mediated cytotoxic and immunostimulatory responses by tumor-induced Mfs. Although tumor-derived factors, including interleukin-10 and transforming growth factor-b1, modulate Mf response to activation signals, paclitaxel partly reverses tumor-induced Mf-mediated suppression of T-cell reactivity through enhanced production of the immunostimulatory cytokine interleukin-12 (IL-12). Concurrently, paclitaxel induces Mf cytotoxic and proinflammatory molecule production, including tumor necrosis factor-a and interleukin-1b. In contrast to its apparent immunotherapeutic effect on Mf populations, paclitaxel's cytostatic mechanisms suppress lymphocyte proliferation and function. We showed that IL-12 can reverse paclitaxel-mediated suppression of T-cell responses in vitro, establishing the foundation for a novel antitumor therapy using paclitaxel in combination with IL-12. We show that the administration of paclitaxel as a chemotherapeutic agent, followed by IL-12 as an immunotherapeutic agent to alleviate paclitaxel-mediated immunosuppression, prolongs survival, reduces tumor progression, and activates immune effector populations in a murine tumor model. These results are the first experimental evidence to suggest that paclitaxel and IL-12 are an effective antitumor modality. Collectively, these studies show that paclitaxel induces multiple antitumor mechanisms that can be enhanced with proper ancillary administration of immunotherapeutic cytokines.
- Doctoral Dissertations