Dendritic Cell-Induced Th1 and Th17 Cell Differentiation for Cancer Therapy

Abstract

The success of cellular immunotherapies against cancer requires the generation of activated CD4⁺ and CD8⁺ T-cells. The type of T-cell response generated (e.g., Th1 or Th2) will determine the efficacy of the therapy, and it is generally assumed that a type-1 response is needed for optimal cancer treatment. IL-17 producing T-cells (Th17/Tc17) play an important role in autoimmune diseases, but their function in cancer is more controversial. While some studies have shown a pro-cancerous role for IL-17, other studies have shown an anti-tumor function. The induction of polarized T-cell responses can be regulated by dendritic cells (DCs). DCs are key regulators of the immune system with the ability to affect both innate and adaptive immune responses. These properties have led many researchers to study the use of ex vivo manipulated DCs for the treatment of various diseases, such as cancer and autoimmune diseases. While Th1/Tc1 cells are traditionally used for their potent anti-tumor responses, mounting evidence suggests Th17/Tc17 cells should be utilized by themselves or for the induction of optimal Th1 responses. It is therefore important to understand the factors involved in the induction of both type-1 and type-17 T-cell responses by DCs.

Keywords: cancer; dendritic cell vaccine; immunotherapy.

Figure 1

Dendritic cell induced Th1 and Th17 immune responses. Toll-like receptor (TLR) ligands are used to mature dendritic cells, and depending on the ligand(s) selected, type-1 dendritic cells (DC1s) or type-17 dendritic cells (DC17s) result. DC1s are characterized by the production of IL-12p70 and induce Th1 immune responses with interferon-γ, granzyme A/B, or perforin secretion. DC17 cells are characterized by the production of a number of cytokines, including IL-23, IL-6, IL-1β and TGF-β, and polarize Th17 immune responses with IL-17A/F, IL-22 and IL-21 production. The cytokines denoted with an asterisk (*) have been reported in the literature to have a role in inducing human Th17 cell differentiation, though there are conflicting reports, and it remains unclear precisely which cytokines are in fact necessary. Finally, there is a third population of T-cells that can be induced by dendritic cells that secrete both IFNγ and IL-17, though the exact mechanism of their differentiation and whether they are directly induced by DCs or are the result of a conversion from Th1 or Th17 cells has yet to be elucidated.