NK Cells: Key to Success of DC-Based Cancer Vaccines?

Abstract

After completing this course, the reader will be able to:1. Describe the current in vivo experimental and clinical dendritic cell (DC) vaccination studies encompassing the monitoring of natural killer (NK) cells.2. Discuss the evaluation of NK cell stimulating potency in the design of DC-based cancer vaccines in the preclinical phase and in clinical trials. Explain the added value of immune monitoring of NK cells in cancer vaccination trials.This article is available for continuing medical education credit at CME.TheOncologist.com. CME CME ABSTRACT NATURAL KILLER CELLS IN CANCERIn the early 1980s, the role of natural killer (NK) cells in defense against cancer was described in seminal reviews [1,2]. A myriad of reports rapidly followed, supporting the involvement and therapeutic potential of NK cells in cancer immunity [3,4]. A range of solid tumors [5][6][7][8][9][10][11][12] and hematological malignancies [13][14][15][16][17][18][19] were shown to be associated with significantly impaired NK cell functions. Importantly, NK cell abnormalities have been shown to be, at least in part, responsible for the failure of antitumor immunity. Deficiencies can reside in all NK cell populations, located in peripheral blood, in (lymphoid) organs, and in the tumor itself [16]. Functional impairment can originate from (a) primary NK cell dysfunction (e.g., imbalanced NK cell receptor expression, impaired cytolytic capacity, reduced cytokine secretion potency), (b) insufficient interaction with other immune cells (e.g., impaired killing of dendritic cells [DCs]) [14], (c) active immune suppression (e.g., regulatory T cell [Treg]-mediated suppression) [20,21], and (d) NK cell resistance mechanisms by tumor cells (e.g., shedding of decoy molecules for activating receptors) [22]. In this regard, multiple cancer studies point toward a prognostic value for NK cells. Table 1 summarizes valuable NK cell parameters used for prognosis of disease progression and patient survival as well as for prediction of therapy efficacy.In humans, NK cells are characterized by a CD56 ϩ CD3 Ϫ NKp46 ϩ phenotype. Based on their CD56 cell-surface density, they can be divided into two subsets with distinct phenotypic properties and key effector functions [23]. The majority (ϳ90%) of peripheral blood NK cells have a CD56 dim CD16 bright phenotype and were originally regarded as the more naturally cytotoxic subset, characterized by high cytotoxic granule and perforin expression and lower cytokine-secreting capacity. The smaller CD56 bright CD16dim/Ϫ NK cell fraction (ϳ10%) constitutively expresses a higher number of cytokine and chemokine receptors and a lower amount of cytotoxic granules, generally showing a poorer cytotoxic capacity but a superior ability to produce abundant immunoregulatory cytokines following activation, in particular the prototypic cytokine interferon (IFN)-␥. Remarkably, these seemingly subtype-specific effector functions appear to be not as restricted as previously thought. Several research groups recently demonstrated that CD56 d...

NK Cell Activation in the Antitumor Response Induced by IFN-α Dendritic Cells Loaded with Apoptotic Cells from Follicular Lymphoma Patients

“…A strong rationale for assuming that DC-mediated NK cell activation contributes to the development of a potent innate response and subsequent adaptive immunity is offered by a growing number of studies (37,38), as well as by some investigators who recently emphasized the key role of NK cells in DC-based cancer vaccines (39,40). Few DC vaccine studies have attempted to evaluate the potential clinical relevance of the NK cell response in the context of DC-based cancer vaccine trials, whereas T cell responses correlate with clinical outcome in only a minority of vaccinated patients (41).…”

Natural killer cell immune escape in acute myeloid leukemia

“…4,9 In general, supporting the NK cell regulatory function was demonstrated to be important for crosstalk with DC and T cells to boost adaptive immunity. 4,11,107 Hence, exploitation of the NK cell-immune cell interactions in the conception of cancer immunotherapy needs to be further assessed in the future. Trafficking of functional NK cells into the tumor site or into an immune cell-enriched environment to promote contact with malignant cells or immune cells is essential for the success of NK cell-directed approaches.…”

Combination Strategies to Enhance the Potency of Monocyte-Derived Dendritic Cell-Based Cancer Vaccines

“…NK cells are also emerging as essential contributors to antitumor immune responses [76] and their activation may be targeted by DC-based vaccines [78]. The 'IL-15 DC,' human monocyte-derived DC differentiated with GM-CSF and IL-15, potently stimulate NK cell antitumor activity in an IL-15-and contact-dependent manner [79], suggesting that DC-based vaccine strategies are also viable options as coordinate activators of antitumor NK cells and T cells.…”