Inciting the cellular arm of adaptive immunity has been the fundamental goal of cancer immunotherapy strategies, specifically focusing on inducing tumour antigen-specific responses by CD8+ cytotoxic T lymphocytes (CTLs). However, there is an emerging appreciation that the cytotoxic function of CD4+ T cells can be effective in a clinical setting. Harnessing this potential will require an understanding of how such cells arise. In this study we use an IL-12 transduced variant of the 70Z/3 leukemia cell line in a B6D2F1 (BDF1) murine model system to reveal a novel cascade of cells and soluble factors that activate anti-cancer CD4+ killer cells. We show that natural killer T (NKT) cells play a pivotal role by activating dendritic cells (DCs) in a contact-dependent manner; soluble products of this interaction, including MCP-1, propagate the activation signal culminating in development of CD4+CTL that directly mediate an anti-leukemia response while also orchestrating a multi-pronged attack by other effector cells. A more complete picture of the conditions that induce such a robust response will allow us to capitalize on CD4+ T cell plasticity for maximum therapeutic effect.
- Received November 27, 2013.
- Revision received July 7, 2014.
- Accepted August 6, 2014.
- Copyright © 2014, American Association for Cancer Research.