By
From the * Department of Dermatology, University of Erlangen-Nürnberg, D-91054 Erlangen,
Germany; and Laboratory of Cellular Physiology and Immunology, The Rockefeller University,
New York 10021
Animal experiments as well as
clinical experience, notably in melanoma, indicate that the
immune system can recognize and kill tumor cells. In particular, CTLs recognize MHC class I-peptide complexes
on the tumor cell surface, and the peptides are derived from nonmutated or mutated genes that can be primarily
expressed in the tumors (1). Why then does the immune
system fail to eradicate most antigenic cancers? One clue is
the observation that CTLs for melanoma and other human
tumors are not known to be expanded. For example, CTL
precursors are not increased in melanoma patients, whereas
humans who are infected with a virus like influenza frequently show expansions in virus-specific CTLp. Therefore tumors have antigens for T cells, but these do not appear to be immunogenic in vivo.
One
possible reason for a lack of tumor immunity is that the antigens are not being presented by dendritic cells (DCs).
DCs are antigen-presenting cells that are specialized to
prime helper and killer T cells in vivo (recently reviewed in
references 4 and 5). To do so, DCs perform a series of coordinated tasks. Immature DCs develop from hematopoietic progenitors and are strategically located at body surfaces
and in interstitial spaces of most tissues. There, DCs are
equipped to capture antigens and to produce large numbers
of immunogenic MHC-peptide complexes. In the presence of maturation-inducing stimuli such as inflammatory
cytokines or stimulation via CD40 (6), DCs upregulate adhesion and costimulatory molecules to become more potent, terminally differentiated, stimulators of T cell immunity. At the same time, numerous intracellular MHC II
compartments seem to discharge MHC II-peptide complexes to the cell surface where they can be unusually long
lived (7, 8). DCs also migrate to secondary lymphoid organs to select and stimulate rare antigen-specific T cells (9, 10).
Nonetheless, there is no evidence that DCs capture and
process antigens from malignant cells in vivo. Tumors, for
example, can make products like IL-10 (11, 12) and vascular endothelial growth factor (13) that could decrease DCs
development and function. Is a lack of tumor antigen presentation by DCs a major problem in generating T cell-
mediated resistance to tumors in vivo? If so, could DCs be
used as adjuvants to induce strong tumor-specific immunity?
The ability to explore DCs as adjuvants for immunization against tumors emerged with better knowledge
on their growth and development. By applying appropriate
cytokines, such as GM-CSF, one can generate large numbers of DCs ex vivo from mice, rats, and humans (14-23,
and Talmor, M., A. Mirza, S. Turley, I. Mellman, L.A.
Hoffman, and R.M. Steinman, manuscript submitted for
publication). Therefore, autologous DCs from tumor-bearing patients can be expanded ex vivo, charged with tumor
antigens, and reinfused to induce tumor-specific T cells including CTLs. This new approach would bypass the proposed obstacle, i.e., that tumor antigens do not access DCs
in vivo. Prior work using bone marrow-derived murine DCs have shown induction of CTL-mediated tumor immunity and resistance in vivo (see review in reference 24).
Two new papers in this issue of the journal (25, 26) emphasize the treatment of established tumors with DCs and
the use of gene transfection to charge DCs with a model
antigen. Both Specht et al. and Song et al. used the murine
tumor CT26.CL25, a subclone of the CT26.WT BALB/c
undifferentiated colon adenocarcinoma that is stably transduced with Escherichia coli If antitumor immunity can be induced with DCs in
vivo, it should become possible to explore potential obstacles to successful immunotherapy of cancers. For example,
once CTLs are induced, it will then be easier to determine
if the CTLs migrate to the tumor and are activated there,
and if there is a loss of tumor antigen presentation. If one
cannot induce CTLs via DCs, has tolerance to the tumor
antigen been induced?
Clinical trials are now addressing the safety and efficacy
of tumor antigen-charged DCs. Melanoma is being emphasized because this is a prevalent tumor for which many
antigens have been shown to be recognized by CTLs. Several variables have to be addressed to identify optimal strategies, and we would like to consider some of these.
Recent studies have uncovered complexity in the DC lineage with several subsets, functions, and maturation stages
(22, 23, 28, 29). Besides classical immunostimulatory "myeloid" DCs, there may be regulatory fas-ligand bearing
"lymphoid" DCs (30). With respect to the stage that will
prove optimal for immunization, the evidence indicates
that the more potent mature DCs should be prioritized.
The many groups that have demonstrated the efficacy of DCs
in mice have primarily used mature, marrow-derived cells.
Immunostimulatory human DCs are generated from
proliferating CD34+ and from nonproliferating CD14+
progenitors. The CD34+ method uses GM-CSF and TNF- A set of criteria has developed to document the maturation of DCs. MLR stimulatory activity should be strong,
since mature human DCs induce a strong MLR at DC/T
cell ratios of 1:1,000 with stimulation indices of 20 or
more. Mature DCs have large veils or sheet-like processes
that extend in several directions from the cell body. The
phenotype includes expression of CD83 and CD25, and
high levels of CD86 and HLA-DR. When cytokines are
removed, mature DCs are stable, whereas if cells are not
matured, they can revert to adherent macrophages. With
maturation, the DCs also can produce large amounts of IL-12
and become resistant to the suppressive effects of IL-10 on
antigen-presenting function.
In mice, mature DCs induce immunity to tumors after injection by the
subcutaneous or intravenous routes. The optimal injection site for human immunization needs to be determined. It
may be that upon intracutaneous injection, DCs will activate in the draining lymph nodes those T cells that preferentially home back to skin and are therefore most effective
at this site. In mice, recent data indicate that upon intravenous injection, DCs home not only to spleen but also to
liver-draining lymph nodes (32). Direct intranodal injection is another possibility (33), but should not be necessary
given the homing properties of DCs.
The development of strong memory would reduce the
frequency of DC injections, but to date, there has been little work on T cell memory after DC priming in situ.
Strong memory might be facilitated by the fact that MHC
II-peptide complexes can be retained for long periods, providing the DCs themselves with a type of "memory" (7, 8).
Human studies will indicate how long memory persists after DC priming, and how often the DCs will have to be
given to achieve optimal immunity.
For assessing variables that lead to optimal immunogenicity, peptide-pulsed
DCs should be suitable. One can then test if the peptide-specific CTLs also kill the tumor in question and not just
experimental, peptide-pulsed targets. The value of immunizing MHC class II-restricted, CD4+, helper and killer T
cells needs to be explored. Investigators also are studying
many approaches to bypass the MHC restriction that is imposed by the use of peptides. Genetic transduction is one
such approach, as carried out by Song et al. (26) and Specht et al. (25), and will allow the DCs to tailor the peptides
from a tumor antigen so that the peptides can be presented
by any given patient's HLA products. Genetically transduced DC might also express MHC-peptide complexes for
very long periods, which may be vital given recent data on
the relatively short half life of MHC I-peptide complexes
on DCs (8).
A single dose of DCs modified with adenoviral and retroviral vectors can be effective for immunizing tumor-bearing
mice, as shown by the two papers in the current issue. For
repeated vaccinations, induction of antiviral or antivector
immunity may pose problems. Nonviral or modified viral
vectors therefore need exploration.
If exogenous proteins can target MHC I products of human DCs, as described for mouse marrow-derived DCs
(34), recombinant tumor antigens will need to be tested.
An exciting goal is to arm DCs with the full antigenic spectrum of tumor cells. Some reported approaches are to
transduce DCs with tumor-derived RNA (35), to fuse DCs
with whole tumor cells (36), and to induce DCs to phagocytose and present whole tumor cells (Albert, M.L., B. Sauter,
and N. Bhardwaj, manuscript submitted for publication).
Another recent development is the production of monoclonal antibodies that recognize MHC-peptide complexes
(37, 38). This could soon permit researchers to monitor
and optimize the many possible antigen-loading procedures
for DCs.
Pilot experiments (31, 39, 40) suggest that DC injections
are safe, and larger trials are underway. It will be important now to demonstrate immune efficacy, and use these responses as a guide to optimizing this approach. Proving that
immunization has occurred, particularly for CTLs, is not
straightforward. Classical measurements for effector CTLs
in blood (51Cr-release assays) may be insensitive, whereas
standard precursor frequency measurements are laborious,
especially for kinetic studies. Restimulation in vitro to activate memory CTLs is far from routine with human cells,
but may now be feasible after DC enrichment (41). Novel
quantification methods for CD8+ T cells such as semiautomated ELISPOT analysis (42) and binding of tetrameric
MHC-peptide complexes (43) should be tested.
There are animal models in
which it is difficult to reject established tumors with immune activated T cells (44). After DC-based immunization
procedures are established, it will be possible to investigate
potential obstacles to the efficacy of tumor-specific CTLs.
Ancillary strategies may be required, for example, to (a) mobilize and activate the immune T cells in the tumor, (b)
obviate tumor-mediated resistance as by expression of fas
ligand (45) and inhibitory cytokines (12, 13), and (c) reverse
the downregulation of antigen presentation that can occur
(46, 47). Supplemental anti tumor approaches such as inhibitors of proteases (48) and angiogenesis (49) may be necessary.
The new animal experiments in this issue indicate
that DC therapy for established tumors can be a significant
strategy. Clinical studies of DC therapy for existing tumors
and DC vaccination at the time that a primary tumor is removed should both be considered. Current methods for
DC-based immunization are within the realm of other cell
therapies in terms of feasibility.
It is also possible that ex vivo generation of DCs will be
superseded by methods to effectively load DCs with tumor
antigens in situ, and to activate their stimulatory and migratory functions. Antitumor immunity may develop if DCs
(or other cells) are substantially expanded in vivo by, e.g.,
flt3 ligand (50). A recent report even reveals that DCs
themselves can have an NK-like, cytolytic activity on certain targets (51).
We have emphasized human studies here, but the careful
animal experiments of Specht et al. and Song et al. in this
issue illustrate that a lack of tumor antigen presentation by
DCs can be an important cause for the absence of T cell-
mediated resistance in tumor-bearing hosts. Additionally,
the ex vivo and genetic transduction approaches in these two
papers are of wide interest for human studies. This is an intriguing time for using DCs to actively manipulate the immune
response to tumors and other clinically important antigens.
-galactosidase as a model antigen. After intravenous inoculation of CT26.CL25 tumor
cells and formation of lung metastases, no
-galactosidase- specific CTLs were noted. However, after a single intravenous or subcutaneous injection of 4-5 × 105 antigen-bearing DCs, (a) a specific CTL response was induced, (b) the
number of lung metastases decreased, and (c) survival was
improved. The DCs were generated from marrow progenitors (Song et al. also used a murine epidermis-derived DC
line) and transduced with the
-galactosidase gene via retroviral (25) or adenoviral (26) vectors. These findings illustrate the lack of tumor antigen presentation in vivo and its
reversal with tumor antigen-charged DCs. It is now necessary to study authentic tumor antigens, rather than models
like
-galactosidase. Interesting other new strategies for the
induction of tumor immunity, such as naked DNA encoding tumor antigens and cytokine-transfected tumor cells, are
also dependent on the presenting function of host DCs (27).
as cytokines, and either bone marrow, cord blood, or adult
blood as a source of progenitors (16). Adult blood is the
most accessible, but requires G-CSF pretreatment of the
patient to increase the otherwise minimal percentage of CD34+ cells. The CD14+ method uses GM-CSF and IL-4
as key cytokines (22, 23), and the abundant monocyte fraction as the starting population. One variable among labs is
the type of serum that is being used, FCS versus human serum or plasma. FCS batches vary considerably in efficacy,
and batches that are LPS-free do not appear to work well
(Schuler, G., unpublished data). For therapy, FCS also
might be infectious and immunogenic, and it therefore
should be avoided, especially since it is feasible to generate
potent DCs in the absence of FCS (21). Hsu et al. (31)
also have used preformed DCs from blood, vaccinating B cell
lymphoma patients with the Ig idiotype from the tumor.
Address correspondence to Dr. R.M. Steinman, Laboratory of Cellular Physiology and Immunology, The Rockefeller University, 1230 York Avenue, New York, NY 10021. Phone: 212-327-8106; FAX: 212-327-8875; E-mail: steinma{at}rockvax.rockefeller.edu
Received for publication 3 September 1997.
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