Murine Splenic CD4+ T Cells, Induced by Innate Immune Cell Interactions and Secreted Factors, Develop Antileukemia Cytotoxicity

Abstract

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 þ cytotoxic T lymphocytes (CTL). However, there is an emerging appreciation that the cytotoxic function of CD4 þ 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 (BDF 1 ) murine model system to reveal a novel cascade of cells and soluble factors that activate anticancer CD4 þ killer cells. We show that natural killer T cells play a pivotal role by activating dendritic cells in a contactdependent manner; soluble products of this interaction, including MCP-1, propagate the activation signal, culminating in the development of CD4 þ 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 þ T-cell plasticity for maximum therapeutic effect.

Interleukin-15 in cancer immunotherapy: IL-15 receptor complex versus soluble IL-15 in a cancer cell-delivered murine leukemia model

“…Numerous animal tumor models have demonstrated broad anti-tumor activity for various cytokines, including GM-CSF, IL-2, IL-7, IL-12, IL-15, IL-18 and IL-21 [1, 2]. Previously we demonstrated that IL-12 is an ideal candidate for leukemia immunotherapy [3, 4] and a phase I clinical trial is currently testing this approach in leukemia patients. In this study we have investigated the potential of interleukin-15 (IL-15) as an immunomodulator in an intraperitoneal cell-delivered leukemia mouse model.…”

Cryo-thermal therapy induces macrophage polarization for durable anti-tumor immunity

“…On the other hand, cryo-thermal therapy triggered M1 macrophage polarization in treated mice on day 5 and efficiently induced M1 macrophage differentiation on day 14. Long-term memory anti-tumor immunity can be generated when the right cells and soluble cytokines are present 36 . When the innate immune cells exhibiting proper immune-stimulatory function were presented, the re-educated macrophages and reshaped DCs, as important initiators, determined the CD4 + T-cell differentiation and CD8 + T-cell cytotoxicity 27 , and a robust T-cell-mediated long-lasting immune response was generated.…”

Cryo-thermal therapy inducing MI macrophage polarization created CXCL10 and IL-6-rich pro-inflammatory environment for CD4+T cell-mediated anti-tumor immunity

“…Cytokines and chemokines are required for activation, differentiation and migration of immune cells [37,38]. In an immunostimulatory environment, pro-inflammatory immune cells, especially DCs and macrophages can activate CD4 þ and CD8 þ T cells to mediate tumor killing [39,40].…”

“…Systemic DC activation modulates immunosuppression and shapes the long-lived memory T cells [42]. However, matured DCs would be generated when the right cells and soluble factors are presented [37]. CXCL10 acts as a chemoattractant for DCs and contributes to DCs maturation and activation [34,35].…”