By
From the * Department of Immunohematology and Blood Bank, Leiden University Medical Center,
2333 AZ Leiden, The Netherlands; and Abteilung Immunologie, Institut für Zellbiologie,
D-72076 Tübingen, Germany
The specificity and power of the cellular arm of the immune system may provide new therapeutic approaches
to cancer. With the assumption that T cells might be able
to recognize and eliminate cancer cells with the same efficiency as virus-infected cells, investigators have searched
many years for ways to trigger or amplify the patient's inadequate immune response to tumors. Much attention has
been given to the role of CD8+ CTLs because most tumors
are MHC class I positive, but negative for MHC class II.
Moreover, CD8+ CTLs are able to lyse tumor cells directly
upon recognition of peptide-MHC class I complexes expressed by the tumor, and their ability to eradicate large tumor masses in vivo has been demonstrated. The focus in
cancer immunology on CD8+ T cell responses is also exemplified by an increasing list of tumor antigens identified
by tumor-reactive CD8+ CTLs. CD4+ Th cells have received far less attention, which is remarkable given the pivotal role of these cells in regulating most antigen-specific immune responses. Until now, only a few Th epitopes derived from human tumor antigens recognized by CD4+ Th
cells have been identified (1, 2). Three studies published in
this issue describe the identification of melanoma antigens that are recognized by CD4+ T cells in the context of
MHC class II molecules (3). Charting the Th response
against human melanoma as well as other tumors is important for the development of optimal anticancer vaccines and for the design of other T cell-related therapeutic modalities in cancer.
Studies using
adoptively transferred purified T cell subsets or in vivo depletion studies have firmly established an important role for
tumor-specific CD8+ CTLs in antitumor immunity (for a
review, see reference 6). By comparing the relative contribution of CD4+ and CD8+ T cells to the overall immune
response, it was shown that activated adoptively transferred
CD8+ T cells alone are as effective as adoptively transferred
CD4+ and CD8+ T cells, provided that IL-2 is given simultaneously (7). Nonetheless, a critical contribution by
tumor-specific CD4+ Th cells in the development of an effective antitumor tumor response was consistently found in
several murine tumor models (10). CD4+ T cells are
likely to play a diversified role in antitumor immunity that
includes several distinct antitumor effector functions. The role of CD4+ T cells in priming of CTLs is well documented (14), explaining why activated CTLs, but not naive
CTLs, can mediate potent antitumor effects in the absence
of CD4+ T cells. Analysis of the participation of individual
T cell populations in the elimination of the Friend murine
leukemia virus (MuLV)-induced tumor FBL-3, revealed
that tumor-specific CD4+ T cells can also exert their effect
independently of CD8+ CTLs. Adoptive transfer studies
showed that both the noncytolytic CD4+ subset as well as
the cytolytic CD8+ subset were individually capable of
eradication of disseminated leukemia in tumor-bearing
mice (for a review, see reference 15). Thus, although the
tumor-specific MHC class II-restricted CD4+ T cells are
not able to recognize this MHC class II-negative tumor directly, they are able to control tumor growth via a mechanism that does not require CTLs (16). More recently, it
was shown that not only adoptive transfer of CD4+ T cells,
but also vaccination with an MuLV-derived Th epitope (but not a control Th peptide) induced protection against a
subsequent challenge with MHC class II-negative, virus-induced tumor cells (17). In this case, the protection induced was dependent on both CD4+ and CD8+ T cells, as
depletion of either subset at the time of tumor challenge abrogated the ability to control tumor outgrowth. Simultaneous vaccination with a tumor-specific CTL epitope and
the tumor-specific Th epitope, rather than an unrelated Th
epitope, resulted in strong synergistic protection. Taken together, these findings illustrate the relevance of identifying
and using tumor-specific Th epitopes even in the case of
MHC class II-negative tumors, and emphasize the importance of activating both tumor-specific CD8+ and CD4+
cells to establish optimal immunity to cancer.
As evident from the experience in the MuLV tumor models, tumor-specific CD4+ T cells can mediate several functions influencing the outcome of tumor-specific
immunity. Numerous studies have focussed on the role
CD4+ T cells play in delivery of help for priming of tumor-specific CTLs, resulting in important mechanistic insights into this event. Accumulating evidence indicates that
for induction of MHC class I-restricted tumor-specific immunity, cross-presentation of antigens that have been captured by professional APCs plays a dominant role (18).
Dissection of the cellular interactions involved in CTL
priming revealed that Th cells must recognize antigen on the same APC that cross-presents the CTL epitope (22).
These findings explain the requirement for epitope linkage
between Th cell epitopes and CTL epitopes important for
induction of CTL responses (23), and could clarify the
view that help for CTLs is delivered through the release of
soluble factors such as IL-2 produced by Th cells in the
proximity of CTLs. Recently, however, it was shown that
T cell help for CTLs is critically dependent on interaction
between CD40L expressed by Th cells and CD40 expressed by APCs (24, 25). Indeed, a central role for CD40-
CD40L interactions in the generation of protective T cell-
mediated tumor immunity has been demonstrated (26, 27).
These interactions most likely empower the APCs to prime
CTLs, since help for CTL priming can be bypassed by activation of dendritic cells (DCs) through CD40 (28). Several
lines of evidence indicate that CD40 signaling is part of an
important pathway in T cell-dependent APC activation. Recombinant soluble CD40L stimulates human monocytes
to release proinflammatory cytokines (29), whereas ligation
of CD40 on DCs or interactions between DCs and CD4+
T cells triggers the production of IL-12. In the latter case, IL-12 production by DCs was inhibited by blockade of
CD40L on the CD4+ T cell (30). Moreover, CD40 ligation is a potent stimulus to upregulate the expression of
intercellular adhesion molecule 1 (ICAM-1), CD80, and
CD86 molecules (31, 32). Because CD40-induced activation of professional APCs results in the expression of costimulatory molecules important for CTL priming, this activation is likely to play an important role in the delivery of
T help to CTLs. In this model, the APC that cross-presents
antigen to both antigen-specific Th cells and CTLs acts as
an intermediary for the delivery of help to CTLs.
Appreciation of the fundamental role of the APC activation state to tune the outcome of T cell responsiveness
helps to explain why CTL responses against tumors, including those induced by noninflammatory persistent tumor viruses such as MuLV (and likely human papillomavirus and Epstein-Barr virus), are dependent on T cell help,
whereas CTL responsiveness against acute disease-causing
cytopathic viruses such as influenza virus is without a clear
need for CD4+ Th activity (33). The difference between
these two situations appears to reside in the fact that influenza virus can directly infect and activate DCs to a phenotype conducive to CTL activation in a CD4+ T cell-independent fashion (28). However, under noninflammatory conditions, such as in many allograft situations and in most
cancers, CTL responses are much more Th cell dependent
because DCs need to be activated first by specific CD4+ T
cells before they trigger T killer responses.
Besides their intimate involvement in priming tumor-specific CTLs, CD4+ Th cells participate in additional effector functions. Evidence that these other Th cell-dependent effector mechanisms play an important role in the host
defence against tumors came from studies in the MuLV system in which adoptively transferred tumor-specific CD4+
T cells are implicated in the activation of tumoricidal macrophages involved in tumor clearance (15). More recently,
it was demonstrated in a model involving vaccination with
irradiated tumor cells, transduced to secrete GM-CSF, that
cytokines produced by CD4+ T cells belonging to the Th1
or Th2 lineage can recruit and activate macrophages and
eosinophils, respectively (13). Protection against tumor
challenge was strongly associated with the presence of eosinophils at the tumor challenge site as well as the production
of oxygen radicals by tumoricidal macrophages, since genetically modified mice disabled to produce these radicals
were severely hampered in their ability to resist tumor
challenge. A significant fraction of CD8 knockout, but not
CD4 knockout animals, were able to successfully resist tumor challenge, indicating that the observed effects relied on CD4+ T cell-mediated effector mechanisms.
As in the MuLV system, the tumor described above did
not express MHC class II molecules, emphasizing the notion that induction or propagation of CD4+ T cell-mediated immunity can be successfully applied to counteract tumors that lack or lose expression of MHC molecules.
The studies
described above, together with the identification of new
tumor antigens recognized by CD4+ T cells, bring fresh
encouragement to the development of anticancer immune
intervention schemes. However, manipulation of the immune response to tumors in tumor-bearing hosts might be
actively frustrated by the tumor itself, as it has been reported that tumors can induce tumor-specific CD4+ T cell
nonresponsiveness (34). The mechanism of tolerization is,
as yet, not clear, but it might mimic many aspects described for tolerance induction to peripheral tissue antigens. Peripheral tolerance induction of both antigen-specific CD4+
and CD8+ T cells to antigens expressed outside the lymphoid system has been described in several models (35).
In these cases, tolerance is mediated by cross-presentation
of the antigen on bone marrow-derived APCs (36, 37). As
development and growth of tumors is initially not accompanied by inflammatory stimuli or stress to the immune system, antigen derived from the tumor might be shunted
in the same cross-tolerizing pathway as reported for peripheral tissue antigens. In this way tumors, as close mimics of
the normal tissue from which they are derived, might
shrewdly use the T cell tolerizing state of certain bone marrow-derived APCs that normally guarantee tissue tolerance. This tolerization of both helpers and killers might
hamper immune intervention schemes that are based on
the induction or propagation of the T cell immune system
in tumor-bearing hosts. Knowledge about the epitopes recognized by human tumor-specific CD4+ and CD8+ T cells
will be instrumental to study whether such a scenario could
explain why certain tumors In summary, tumor-specific CD4+ Th cells can orchestrate several effector functions that can cooperate in an effective antitumor response. Knowledge of the antigens and
peptides recognized by human CD4+ T cells is of crucial
importance for a better understanding of the behavior and
role these cells play in the immune response to human tumors, as well as for optimal use of the Th arm of the immune system in the development of new anticancer
vaccine modalities. The studies published in this issue describing new MHC class II-restricted melanoma antigens
and new methods to identify tumor antigens recognized by
CD4+ T cells point to the vital role CD4+ T cells have in
immune attack directed against human tumors, and will be
of great benefit in optimizing tumor immunotherapy if the
rules of the murine models apply to the situation in cancer patients.
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for instance, melanomaare
able to grow, despite the expression of potentially highly
immunogenic tumor antigens.
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Footnotes |
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Address correspondence to René E.M. Toes, Department of Immunohematology and Blood Bank, Leiden University Medical Center, P.O. Box 9600, 2333 AZ Leiden, The Netherlands. Phone: 31-71-5263800; Fax: 31-71-5216751; E-mail: r.e.m.toes{at}immunohematology.medfac.leidenuniv.nl
Received for publication 13 January 1999.
R.E.M. Toes is a fellow of the Royal Netherlands Academy of Arts and Sciences.We thank Dr. H.G. Rammensee and Dr. T.H.M. Ottenhoff for critical reading of the manuscript.
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