Elsevier

Molecular Immunology

Volume 42, Issue 4, February 2005, Pages 535-539
Molecular Immunology

Review
Helper role of NK cells during the induction of anticancer responses by dendritic cells

https://doi.org/10.1016/j.molimm.2004.07.038Get rights and content

Abstract

Recent reports demonstrate that natural killer (NK) cells and dendritic cells (DC) support each other's activity in a positive feedback. We observed that activated NK cells induce the maturation of DCs into stable type-1 polarized DCs (DC1), characterized by up to 100-fold enhanced ability to produce IL-12p70 in response to subsequent interaction with Th cells. DC1 induction depends on NK cell-produced IFN-γ and TNF-α, with a possible involvement of additional factors. DC1, induced by NK cells or by NK cell-related soluble factors, are stable, resistant to tumor-related suppressive factors, and show strongly enhanced ability to induce Th1 and CTL responses. In analogy to resting T cells, the induction of “helper” function of NK cells relies on a two-signal activation paradigm. While NKG2D-dependent tumor cell recognition is sufficient to induce the cytotoxic “effector” function of NK cells, the induction of “NK cell help” requires additional signals from type-1 IFNs, products of virally-infected cells, or from IL-2. Compared to non-polarized DCs currently-used in clinical trials, DC1s act as superior inducers of anti-cancer CTL responses during in vitro sensitization. The current data provides rationale for the clinical use of DC1s in cancer and chronic infections (such as HIV), as a new generation DC-based vaccines, uniquely combining fully mature DC status with an elevated, rather than “exhausted” ability to produce bioactive IL-12p70. We are currently implementing stage I/II clinical trials, testing the effectiveness of DC1s induced by NK cells or by NK cell-related factors, as therapeutic vaccines against melanoma.

Introduction

Natural killer (NK) cells and dendritic cells (DC) are rapidly recruited to the sites of inflammation (Biron, 1997, Biron and Brossay, 2001, Banchereau and Steinman, 1998). DCs are crucial for the induction of primary immune responses, providing naïve T cells with Ag-specific “signal 1”, and costimulatory “signal 2” (Banchereau and Steinman, 1998). In addition, DCs can also provide an additional “signal 3” (polarization), driving the development of immune responses towards Th1 or Th2 direction (Kalinski et al., 1999a, Moser and Murphy, 2000). Early stages of viral infection are also associated with the recruitment and local activation of NK cells, capable of exchanging bidirectional activating signals with DCs. DC are known to support the tumoricidal activity of NK cells (Fernandez et al., 1999a), while cytokine-preactivated NK cells have been demonstrated to activate DC, induce their maturation and cytokine production (Gerosa et al., 2002, Piccioli et al., 2002, Ferlazzo et al., 2002).

Recent data from us and from other groups demonstrate that such NK–DC interaction promotes the subsequent induction of tumor-specific responses of CD4+ and CD8+ T cells, allowing NK cells to act as “helper” cells in the development of the desirable, inflammatory-type (type-1), responses against cancer.

Section snippets

A difficult choice: mature DCs or DC with high IL-12 producing capacity?

Since mid-1990s, DCs have been increasingly applied as experimental vaccines for cancer patients (Banchereau and Steinman, 1998, Engleman, 2003). Several features of DCs, including their maturation status, migratory potential, and cytokine production, have been shown important for their ability to induce high numbers of Th1-type CD4+ T cells and CD8+ CTLs. The effective induction of anti-tumor CTL responses requires fully-mature DCs that express high levels of costimulatory molecules and which

Clinical applications of DC1NK and αDC1: Phase I/II clinical trials in melanoma and other cancers

The ability of NK cells and their soluble products to polarize DCs allows for the first time for the clinical use of DCs combining fully-mature status and high migratory functions with a strongly-elevated, instead of “exhausted”, ability to produce IL-12p70. We are currently in the process of obtaining the FDA and institutional approvals for stage I/II trials of melanoma vaccines, utilizing DC1NK (UPCI 03-165) and αDC1 (UPCI 03-118 and UPCI 04-042). In addition to these studies, DC1-based

Conclusions and future directions

The above-reviewed data indicate that, in addition to their direct cytotoxic “effector” functions against virally-infected or transformed cells, two-signal activated NK cells also perform “helper” functions, mediated by type-1 polarized DCs. Such DC1 uniquely combine the three features critical for induction of type-1 immunity: (1) fully-mature status; (2) high responsiveness to secondary lymphoid organ chemokines (CCR7 ligands); (3) high IL-12p70-producing ability (Table 1).

While TNFα and IFNγ

Acknowledgements

This work was supported by the grants (to PK) from NCI (1RO1CA82016 and 1RO1CA 095128), from The Melanoma Foundation and from The Pittsburgh Foundation. The authors thank Drs. William Chambers, Hideho Okada, Nikola Vujanovic, Amy Wesa, Pedro Vieira, Martien Kapsenberg, David Bartlett, Michael Lotze, and Ronald Herberman for stimulating discussions.

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