Review
Polarized dendritic cells as cancer vaccines: Directing effector-type T cells to tumors

https://doi.org/10.1016/j.smim.2010.03.002Get rights and content

Abstract

Ex vivo generation and antigen loading of dendritic cells (DCs) from cancer patients helps to bypass the dysfunction of endogenous DCs. It also allows to control the process of DC maturation and to imprint in maturing DCs several functions essential for induction of effective forms of cancer immunity. Recent reports from several groups including ours demonstrate that distinct conditions of DC generation and maturation can prime DCs for preferential interaction with different (effector versus regulatory) subsets of immune cells. Moreover, differentially-generated DCs have been shown to imprint different effector mechanisms in CD4+ and CD8+ T cells (delivery of “signal three”) and to induce their different homing properties (delivery of “signal four”). These developments allow for selective induction of tumor-specific T cells with desirable effector functions and tumor-relevant homing properties and to direct the desirable types of immune cells to tumors.

Introduction

Established therapies of cancer, such as surgery, chemo- and radio-therapy, are usually effective in reducing major tumor mass in patients with established tumors, but often fail to eliminate residual cancer cells and prevent disease recurrence. This particular deficit led to attempts at utilizing patients’ own immune system, specialized in generating sterilizing immunity to invading microbes, in order to identify and destroy persisting cancer cells.

Therapeutic “cancer vaccines” share many features of traditional protective vaccines against microbial pathogens. Similar to protective vaccines they need to induce immune responses of defined specificity and high magnitude. Although tumor cells are less different from the hosts healthy cells than virally-infected cells (what renders them less immunogenic), extensive research of the last 20 years allowed to identify unique tumor unique antigens and the ways of effectively presenting them to the immune system in the context of strong adjuvant signals (delivery of “signal 1” and “signal 2”) [1], [2], [3], [4], [5].

However, despite the increasingly-high immunologic effectiveness of new cancer vaccines and indications of their ability to delay cancer progression [2], [6], [7], [8], [9], the overall effectiveness of the currently-available therapeutic vaccines against cancer still trails the effectiveness of preventive vaccination against infective agents [1], [2], [10], [11], [12], [13], [14], [15], [16]. In particular, while current cancer vaccines show early promise in inducing disease stabilization and prolonging patients’ survival [14], [17], [18], [19], they remain poorly effective in inducing regression of bulky tumors [13]. In this review, we will focus on two aspects of T cell function essential for their ability to induce cancer regression: their cytolytic effector functions and their ability to migrate to tumors, and the corresponding requirements for DC-based vaccines to preferentially support the activity of the effector-type (Teff), rather than regulatory type (Treg) T cell responses, and to deliver to T cells two types of signals regulating the acquisition of effector functions (signal 3) and tumor-relevant homing properties (signal 4).

Section snippets

Therapeutic vaccines against established cancer: special requirements

Several aspects of vaccination relevant to therapeutic vaccines and several types of resulting challenges are less relevant to preventive vaccines, making it less clear whether the paradigms and practices successfully established during the development of protective vaccines are indeed relevant to therapeutic vaccination, in patients with advanced cancer.

The goal of protective vaccines is to induce the expansion of pathogen-specific T cells and establish immune memory (Fig. 1). Subsequent

Ex vivo-generated DC as “cancer vaccines”: benefits and caveats of DC maturation

DCs, the APCs specialized in inducing primary immune responses [58], [59], [60], [61], are also essential in supporting the survival and functions of previously-primed T cells and in mediating overall communication within the immune system [62], [63]. Since in contrast to the DCs that develop in the context of tumor-related suppressive factors, fully-mature DCs acquire significant resistance to such inhibitory factors [64], [65], [66], the therapeutic use of ex vivo-generated DCs became a

Type-1-polarized DCs: mature DCs with elevated, rather than “exhausted” ability to produce type-1-inducing factors and to induce type-1 immunity

Induction of anti-tumor CTL responses by DC-based vaccines benefits from high expression of co-stimulatory molecules and CCR7 responsiveness, typical of mature DCs [69], [70], [79], [84]. At the same time, high IL-12p70 secretion has been shown to dramatically enhance the ability of DCs to induce tumor-specific Th1 cells and CTLs, and to promote tumor rejection in therapeutic mouse models [85], [86], [87], [88], [89], [90], [91], [92], [93], [94], [95]. Unfortunately, obtaining DCs with all the

Preferential interaction of polarized DC1s with the desirable immune cells (CTLs, Th1- and NK cells)

In addition to improving their overall immunostimulatory function, another aspect that needs a thorough evaluation is the possibility to manipulate vaccines to selectively enhance the interaction of the antigen-carrying DCs with the desirable types of immune cells, such as Th1, NK and CTL (allowing to selectively expand these subsets and support their functions), and to avoid their interaction with suppressor/regulatory cells. The need for such manipulations has been highlighted by the

Selective induction of type-1 immune functions by polarized DC1s (delivery of signal 3)

DCs provide T cells with antigen-specific “signal 1” and co-stimulatory “signal 2” [127], [128], [129], promoting the expansion of tumor-specific T cells. DCs are also known to provide T cells with an additional “signal 3” (polarization; [63]), selectively driving the development of type-1 or type-2 immunity, associated with differential involvement of particular effector mechanisms and different abilities to induce cancer rejection [63], [82], [127], [128], [129], [130], [131], [132], [133],

Induction tumor-relevant homing function in tumor-specific T cells (delivery of signal 4)

The observations of high immunologic activity of many cancer vaccines, combined with their limited effectiveness in inducing cancer regression [13], [141], suggest that the currently used vaccines may be suboptimal in inducing relevant tumor-homing properties in the vaccination-induced T cells, and that the effectiveness of cancer immunotherapies may benefit from the means to enhance the expression of tumor-relevant homing receptors on cancer-specific T cells. The differences in homing

Clinical evaluation of polarized DC1s: towards next generations of DC-based therapies

The clinical activity of type-1-polarized DCs generated in the presence of IFN-α (αDC1s) are being currently evaluated in a variety of cancer types, including glioma, melanoma, colon and prostate cancers at the University of Pittsburgh Cancer Institute (see ClinicalTrials.gov: NCT00390338, NCT00099593, NCT00766753, NCT00558051 and NCT00970203), with the clinical trials of other types of such “third generation” DC-based vaccines ongoing in other centers. In our trials, peptide-, autologous- or

Acknowledgements

The author thank Drs. R. Muthuswamy, P. Watchmaker, E. Berk, T. Reinhart, L. Geskin, J. Kirkwood, K. Chatta and David Bartlett, for stimulating discussions and for sharing unpublished data. This work was supported by the NIH grants CA095128, CA114931, CA101944, CA121773, EA055944, CA137214, NS055140, and NS40923.

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