Dual role of immunomodulation by anticancer chemotherapy

Abstract

The anticancer efficacy of conventional chemotherapies seems to be due, in part, to augmentation of the host immune reactivity. However, a new study reveals that two common chemotherapeutic agents, gemcitabine and 5-fluorouracil, can also activate immune regulatory cells, which stimulates the emergence of protumorigenic cytokines via inflammasome pathways, limiting the antitumor efficacy of the drugs (pages 57–64).

Figure 1

Molecular and cellular pathways of chemotherapy-induced, immune cell–mediated inhibition of antitumor efficacy. The common chemotherapeutic agents gemcitabine and 5-fluorouracil activate a signaling cascade in MDSCs that leads to secretion of IL-1β. Upon cell entry, the drugs are metabolized by kinase-mediated phosphorylation, and the metabolites bind their molecular targets, including the proapoptotic protein Bax, leading to destabilization and disruption of lysosomes and release of cathepsin B. Cathepsin B directly interacts with the leucine-rich-repeat (LRR) domain of NLRP3 inflammasome (which comprises the NLR protein Nlrp3, the adaptor ASC and pro-caspase-1) causing its activation. After its assembly, the inflammasome converts pro-caspase-1 into an active enzyme, which then cleaves pro-IL-1β, a precursor of IL-1β, resulting in the formation of a biologically active cytokine that is released from MDSCs. IL-1β is an important regulator of CD4⁺ T helper cell polarization and drives the emergence of T_H17 subsets, which produce IL-17. Soluble IL-1β may also stimulate MDSC expansion and attraction. Pleiotropic cytokine IL-17 plays an active part in tumor pathogenesis and progression by enhancing the emergence of immunosuppressor MDSCs to the tumor site, reducing tumor infiltration by cytotoxic T cells and inducing intratumor neoangiogenesis. ASC, apoptosis-associated speck-like protein containing a CARD domain.