Inciting the cellular arm of adaptive immunity has been the fundamental goal of cancer immunotherapy strategies, specifically focusing on inducing tumor antigen–specific responses by CD8+ cytotoxic T lymphocytes (CTL). 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 IL12-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 anticancer CD4+ killer cells. We show that natural killer T cells play a pivotal role by activating dendritic cells in a contact-dependent manner; soluble products of this interaction, including MCP-1, propagate the activation signal, culminating in the development of CD4+ CTLs that directly mediate an antileukemia response while also orchestrating a multipronged 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. Cancer Immunol Res; 2(11); 1–12. ©2014 AACR.
- Received November 27, 2013.
- Revision received July 7, 2014.
- Accepted August 6, 2014.
- ©2014 American Association for Cancer Research.