A novel dendritic cell subset involved in tumor immunosurveillance.

The interferon (IFN)-gamma-induced TRAIL effector mechanism is a vital component of cancer immunosurveillance by natural killer (NK) cells in mice. Here we show that the main source of IFN-gamma is not the conventional NK cell but a subset of B220(+)Ly6C(-) dendritic cells, which are atypical insofar as they express NK cell-surface molecules. Upon contact with a variety of tumor cells that are poorly recognized by NK cells, B220(+)NK1.1(+) dendritic cells secrete high levels of IFN-gamma and mediate TRAIL-dependent lysis of tumor cells. Adoptive transfer of these IFN-producing killer dendritic cells (IKDCs) into tumor-bearing Rag2(-/-)Il2rg(-/-) mice prevented tumor outgrowth, whereas transfer of conventional NK cells did not. In conclusion, we identified IKDCs as pivotal sensors and effectors of the innate antitumor immune response.

Killer dendritic cells: IKDC and the others.

Tumors can regress as a result of invading myeloid and lymphoid cells that act in concert. Although the myeloid cells are widely recognized as antigen presenters and lymphoid cells as classical effectors, recent evidence revealed the capacity of dendritic cells (DC) to kill tumor cells. The functional concept of 'natural killer (NK) myeloid DC' is supported by mouse and human in vitro data that may be clinically relevant because human killer DC can contribute to tumor shrinking during topical therapy with toll-like receptor (TLR) agonists. Whether tumor killing by DC is a 'catalyzing' step for efficient crosspresentation and/or a promoting step for an immunogenic cell death pathway remains an open question. We also discuss how interferon-producing killer DC (IKDC) may participate in the control of tumor progression.

Dendritic cells and innate defense against tumor cells.

Tumor growth results from a delicate balance between intrinsic dysregulation of oncogenes, tumor suppressor and stability genes counteracted by extrinsic defenses composed of immune cells shaping tumor immunogenicity. Although immune subversion might be the ultimate outcome of this process, a complex network of cellular interactions take place eventually leading to tumor specific cognate immune responses. The links between innate and cognate antitumor immunity eliciting protective T cell responses are instigated by cytokines, chemokines and damage associated molecular patterns. The intricate differentiation pathway whereby dendritic cells could undergo an efficient maturation program in the tumor microenvironment appears crucial. We will discuss the role of innate effectors and cancer therapies in the process of defense against tumor cells.

Therapy-induced tumor immunosurveillance involves IFN-producing killer dendritic cells.

A unique class of IFN-producing killer dendritic cells (IKDC) resembling natural killer cells has been defined that can recognize and lyse tumor cells through a tumor necrosis factor-related apoptosis-inducing ligand-dependent mechanism. IKDC may mediate the host-dependent antitumor activity of Gleevec/STI571 and other therapeutics that can inhibit the c-kit tyrosine kinase. IKDC represent an important new component of the innate immune system responding to cancer.

Interferon-gamma is produced by another player of innate immune responses: the interferon-producing killer dendritic cell (IKDC).

Interferon-gamma is a key cytokine in tumor immunosurveillance. The recently described interferon-producing killer dendritic cell (IKDC), can be distinguished from other innate effectors by its ability to kill a large variety of tumor cells and to produce high amounts of interferon-gamma after encountering tumors in the absence of exogenous cytokines. The cytotoxic activity of IKDC was unraveled during an efficient immunotherapy combining c-kit tyrosine kinase inhibitors and interleukin-2, and is mediated through tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and interferon type IIR.

The dendritic cell-like functions of IFN-producing killer dendritic cells reside in the CD11b+ subset and are licensed by tumor cells.

IFN producing killer dendritic cells (IKDC) were originally defined as CD11c(int) B220(+)NK1.1(+) (or CD49b(+)) cells that exert a potent tumoricidal activity in animals lacking B, T, and conventional natural killer effectors. MHC class II expression on tumor infiltrating IKDC prompted us to investigate their putative antigen presenting function. Here, we show that tumor cells license IKDC to acquire the properties of antigen presenting cells, i.e., expression of MHC class II and costimulatory CD86 molecules. We show that the CD11b(+) subset of IKDC are able to prime naïve CD4(+) T cells and cross-prime naïve CD8(+) T lymphocytes. Licensing of IKDC by tumor cells was mandatory for the full differentiation of T cells into polarized effectors. IKDC could engulf and process soluble Ova protein in a CD206-dependent manner. Finally, we show that CD11b(+)IKDC is selectively endowed with CTLA4Ig-inhibitable antigen presenting capacities and that targeting this subset with the detoxified adenylate cyclase toxin of Bordetella pertussis fused to antigen resulted in efficient cross-presentation of antigen by IKDC to specific TCR transgenic CD8(+)T cells in vivo. Collectively, our data indicate that upon exposure to tumor cells, IKDC subserve DC-like functions.

Trans-presentation of IL-15 dictates IFN-producing killer dendritic cells effector functions.

IFN-producing killer dendritic cells (IKDC) were initially described as B220(+)CD11c(+)CD3(-)NK1.1(+) tumor-infiltrating cells that mediated part of the antitumor effects of the combination therapy with imatinib mesylate and IL-2. In this study, we show their functional dependency on IL-15 during homeostasis and inflammatory processes. Trans-presentation of IL-15 by IL-15Ralpha allows dramatic expansion of IKDC in vitro and in vivo, licenses IKDC for TRAIL-dependent killing and endows IKDC with immunizing potential, all three biological attributes not shared by B220(-)NK cells. However, IL-15 down-regulates the capacity of IKDC to induce MHC class I- or II-restricted T cell activation in vitro. Trans-presentation of IL-15 by IL-15Ralpha allows IKDC to respond to TLR3 and TLR4 ligands for the production of CCL2, a chemokine that is critical for IKDC trafficking into tumor beds (as described recently). We conclude that IKDC represent a unique subset of innate effectors functionally distinguishable from conventional NK cells in their ability to promptly respond to IL-15-driven inflammatory processes.

The critical role of IL-15 in the antitumor effects mediated by the combination therapy imatinib and IL-2.

The synergistic antitumor effects of the combination therapy imatinib mesylate (IM) and IL-2 depended upon NK1.1- expressing cells and were associated with the accumulation of CD11c(int)B220(+)NK1.1(+) IFN-producing killer dendritic cells (IKDC) into tumor beds. In this study, we show that the antitumor efficacy of the combination therapy was compromised in IL-15 and IFN-type 1R loss-of-function mice. IL-15Ralpha was required for the proliferation of IKDC during IM plus IL-2 therapy. Trans-presentation of IL-15/IL-15Ralpha activated IKDC to express CCR2 and to respond to type 1 IFN by producing CCL2. Moreover, the antitumor effects of the combination therapy correlated with a CCL2-dependent recruitment of IKDC, but not B220(-) NK cells, into tumor beds. Altogether, the IL-15-driven peripheral expansion and the CCL-2-dependent intratumoral chemoattraction of IKDC are two critical parameters dictating the antitumor efficacy of IM plus IL-2 in mice.