Human tumor-specific T lymphocytes: does function matter
more than number?
Pierre G Coulie and Thierry Connerotte
In recent years, several clinical trials have involved the
vaccination of cancer patients with tumor-specific antigens
that are recognized by T lymphocytes. Anti-vaccine T-cell
responses in these patients have been monitored on the
assumption that their magnitude would correlate with clinical
efficacy. Although analysis of these data show that such a
correlation is emerging, detailed analyses of the few patients
who benefit clinically from the vaccinations suggest that the
function of the anti-vaccine T cells might be more important
than their number. Recent studies show that in cancer patients
numerous tumor-specific T cells appear to be quiescent in the
presence of the tumor. Understanding how an efficient vaccine
interferes with this coexistence is one of the current challenges
of cancer immunotherapy.
Institute of Cellular Pathology and Universite ´ catholique de Louvain,
Avenue Hippocrate 74, UCL 7459, B-1200 Brussels, Belgium
Corresponding author: Coulie, Pierre G (firstname.lastname@example.org)
Current Opinion in Immunology 2005, 17:320–325
This review comes from a themed issue on
Lymphocyte effector functions
Edited by Lorenzo Moretta
Available online 11th April 2005
0952-7915/$ – see front matter
# 2005 Elsevier Ltd. All rights reserved.
Human T lymphocytes that recognize tumor-specific
antigens have become amenable to precise immunologi-
cal analysis as a result of the identification of a wide
variety oftumor-specificantigens and thedevelopment of
tetramer technology. Clinical trials using vaccines com-
prising well-defined tumor antigens are usually followed
by an analysis of the anti-vaccine T-cell response in
search of a meaningful surrogate marker of clinical effi-
cacy. But even though several methods can be used to
estimate the frequencies of human anti-vaccine T cells,
only few studies have tried to establish a correlation
between the detection of T-cell responses and clinical
outcomes in vaccinated patients. The first part of this
review summarizes these studies; the second part of this
review focuses on the notion that high frequencies of
tumor-specific T cells do not guarantee therapeutic effi-
cacy, and that the function of these lymphocytes could
matter more than their number.
Before discussing the numbers and functions of tumor-
specific T cells in the context of therapeutic vaccination,
it is important to remember that an optimal T-cell
response will not lead to rejection of a tumor that has
become resistant to immune attack because of loss of
antigen expression or other mechanisms. In a recent
clinical trial combining conditioning chemotherapy,
transfer of anti-tumor T cells and IL-2 therapy, 18 out
of 35 melanoma patients experienced a clinical response
[1?]. This observation indicates that at least 50% of
melanoma tumors cannot completely resist immune
Frequency of tumor-specific anti-vaccine
T cells: does number count?
Clinical studies of anti-tumoral vaccination have been
monitored on the premise that massive anti-vaccine T-
cell responses are required for tumor rejection. In mice
vaccinated with tumor antigens, the intensity of anti-
vaccine T-cell responses appears to correlate with clinical
efficacy [2,3]. Is this also observed in patients?
Estimating the frequency of human tumor-specific
Only a few methods are available to estimate the fre-
quencies of T cells that recognize particular defined
tumor antigens. A direct estimation of this frequency
can be obtained using ex vivo assays such as tetramer
labeling or cytokine secretion measured by Elispot, pro-
vided that the frequency exceeds a threshold of about
5 ? 10?4of the CD4+or CD8+T cells present. To detect
T cells at lower frequencies the lymphocytes have to be
amplified first by re-stimulation in vitro with the antigen.
This results in two difficulties. Firstly, a frequency can
only be estimated if re-stimulation is carried out in limit-
ing dilution conditions, which involves a heavy workload.
Secondly, you can only measure the frequency of those
precursors that proliferated enough to generate a detect-
able clonal progeny. This leads to underestimated fre-
It is noteworthy that the absence of detectable T cells in
the ex vivo assays does not exclude the possibility that a
response occurred in vivo. The reason for this is that the
detection threshold of 5 ? 10?4necessary for the ex vivo
assays is 1 000-fold higher than the frequency of naı ¨ve T
HLA-A1 this frequency is 4 ? 10?7of CD8+cells , and
Current Opinion in Immunology 2005, 17:320–325www.sciencedirect.com
we observed similar frequencies for T cells that recognize
gp100, NA17, LAGE-1, or MAGE-A10 antigens. The
Melan-AMART-128–36peptide is a remarkable exception,
with a very high naı ¨ve T cell frequency of about 5 ? 10?4
of CD8+cells .
Frequencies of anti-vaccine T cells
Reported frequencies of anti-vaccine T cells following
immunization with tumor antigens vary from >10?2to
10?6of the total T-cell population. Anti-Melan-AMART-1
T cells were found at frequencies of up to 2 ? 10?2of
CD8+cells in melanoma patients vaccinated with peptide
either in incomplete Freund’s adjuvant (IFA) , or in
IFA with CpG . Anti-gp100209–217cytotoxic T lym-
phocytes (CTLs) were found at >10?2of CD8+cells in
tumor-free melanoma patients vaccinated with peptide in
IFA [8,9]. Anti-MAGE-A3168–176CTLs were present at
3 ? 10?3and 10?3in patients vaccinated with ALVAC-
MAGE or peptide-pulsed dendritic cells (DCs), respec-
tively [10,11]. HLA-DP4-restricted CD4+cells recogniz-
ing peptide MAGE-A3243–258were found at 7 ? 10?4of
CD4+cells after vaccination with peptide-pulsed DCs
. Finally, several patients vaccinated with peptide or
ALVAC-MAGE had monoclonal anti-MAGE-A3168–176
CTL responses at low frequencies of about 10?6of
T-cell responses and clinical outcomes
Very few studies have analyzed whether these anti-vac-
cine T-cell responses correlate with the observed tumor
regressions [4,6,13,14] (Table 1). A correlation seems to
emerge from two studies [4,6], compatible with the
hypothesis that the anti-vaccine T-cell response is neces-
sary, but not in itself sufficient, to initiate tumor rejection.
A tight correlation is unlikely to be found for two reasons.
First, some patients have strong anti-vaccine T-cell
responses without detectable clinical benefit. It is certain
that a limitingfactor forclinicalefficacy, in addition to the
frequency of anti-vaccine T cells, is tumor resistance to
immune attack. Second, and perhaps more surprisingly,
some patients display tumor regression with no or very
few detectable anti-vaccine T cells . In such patients,
tumor-specific CTLs that recognized antigens absent
from the vaccine were primed or amplified after vaccina-
tion [15?]. In regressing metastases, these anti-tumor
CTLs were 10 000 times more frequent than the anti-
vaccine T cells and, therefore, probably effected tumor
rejection [16?]. These results are in line with those of
other groups that described post-vaccination T cells
which recognized tumor antigens that were absent from
the vaccine [17–19]. A plausible model is that anti-vac-
cine T cells, even at very low frequencies, modify an
immunosuppressive environment within the tumor,
opening a permissive window for the priming or re-
stimulation of other anti-tumor T cells.
Functions of anti-tumor T cells: what is
High frequencies of anti-tumor T cells, present either
after vaccination  or after spontaneous anti-tumor
responses [15?], do not secure tumor regression. The
coexistence of tumor cells and primed tumor-specific T
Tumor-specific T lymphocytes: function or number? Coulie and Connerotte321
Studies addressing the correlation between immunological and clinical responses in metastatic melanoma patients with detectable
disease and vaccinated with defined tumor antigens.
Reported T cell responses in patients with:
regression of ?1
Method of monitoring
anti-vaccine T cells
No evidence of
Peptide + IFA
2/21ex vivo tetramer/
ex vivo elispot
ex vivo elispot
ex vivo elispot
aALVAC-MAGE is a recombinant canarypox virus of the ALVAC type carrying a minigene coding for two antigenic peptides: MAGE-A3168–176
and MAGE-A1161–169.bDendritic cells derived from adherent blood mononuclear cells cultured with GM-CSF and IL-4 and matured by
monocyte-conditioned medium.cDendritic cells derived from circulating CD34+ precursor cells mobilized by G-CSF, cultured with GM-CSF,
FLT3-L and TNF.dMixed lymphocyte–peptide cultures in which blood mononuclear cells are stimulated with peptide over two weeks, followed
by labeling with tetramer. Anti-vaccine CTL clones are cloned from the tetramer-positive cells.eIn this study, 6/7 clinical regressors and 3/11
clinical progressors responded to at least three of the four antigens. Abbreviations: FLT3-L, fms-related tyrosine kinase 3 ligand; G-CSF,
granulocyte colony stimulating factor; GM-CSF, granulocyte-macrophage colony stimulating factor.
Current Opinion in Immunology 2005, 17:320–325
cells can result from at least two mechanisms: tumor
resistance and lymphocyte quiescence (Box 1).
The mechanisms of tumor resistance to fully competent
lymphocytes display a diversity beyond the scope of this
review. We have selected two recent observations to
discuss here. The first deals with a function of the
anti-tumor T cells themselves; namely the production
of IFN-g. This cytokine induces the change of standard
proteasomes into immunoproteasomes, which differ by
the three catalytic subunits and therefore produce a
different spectrum of peptides. If a tumor antigen can
be processed by the standard proteasome, but not by the
cells will inhibit this processing. This might apply to the
Melan-AMART-1peptide . At first, T-cells proliferate
after recognizing the peptide on tumor cells. But then the
IFN-g that they produce downmodulates antigen expres-
sion. This scenario might explain the coexistence of
melanoma cells with high numbers of anti-Melan-
A second mechanism of tumor resistance involves the
barriers put up by the tumor vasculature that do not
permit lymphocyte infiltration . In mice, the systemic
application of CpG greatly increases the infiltration of
transferred T cells into tumors [23?]. This strategy could
be combined with vaccination in patients.
A few years ago, Lee et al.  reported that anti-tyro-
sinase blood CD8+T lymphocytes were functionally
deficient; that is, they did not lyse when analyzed directly
ex vivo. A recent study by the Romero group [25??]
showed that anti-Melan-AMART-1T cells present in meta-
static lymph nodes of melanoma patients did not produce
IFN-g after ex vivo re-stimulation with peptide. Interest-
ingly, this defect was reversible after culturing the cells
for two days with IL-2 and IL-7. Anti-Melan-AMART-1T
cells from the blood of the same patients were not
deficientin IFN-gproductionwhen re-stimulated ex vivo.
Finally, anti-cytomegalovirus (CMV) T cells found
in metastatic lymph nodes were also not deficient in
IFN-g [25??]. These results define a state of primed T
lymphocyte quiescence that is reversible, localized and
Causes of lymphocyte quiescence
There are certainly several causes of such a quiescence,
which is sometimes referred to as functional tolerance or
paralysis. One possibility is the lack of a soluble factor
necessary for complete T-cell function; for example,
tryptophan shortage prevents T-cell proliferation .
Tryptophan is degraded by indoleamine 2,3-dioxygenase
(IDO), which is expressed in many tumors and provides
them with a mechanism to resist immune attack, even in
an immunized animal [27?]. IDO is also expressed by
murine plasmacytoid DCs in tumor-draining lymph
nodes , where it could be responsible for local immu-
Another candidate for the cause of quiescence is arginine,
as arginine starvation decreases the half-life of CD3z
mRNA and inhibits T-cell proliferation in vitro [29,30].
Arginase I, which metabolizes arginine, was detected in
suspensions of human non-small-cell lung cancer cells,
which also contained T cells with a decreased expression
of CD3z compared to allogenic lymphocytes .
Finally, a local shortage of IL-2 could be another impor-
tant factor in inducing lymphocyte quiescence. There are
several recent additions to the numerous studies on the
role of IL-2 for anti-tumor T-cell function. In mice,
exogenous IL-2 is a crucial factor for treating established
tumors by T-cell adoptive transfer . In patients, low-
dose IL-2 prolongs the persistence of transferred anti-
tumor T-cell clones . In patients chronically infected
with HIV-1, virus-specific CD8+T cells appeared to be
quiescent; that is, they fail to proliferate in vitro after
stimulation with the antigen. Addition of autologous anti-
HIV-1 CD4+cells restored this proliferation, but not in
the presence of neutralizing anti-IL-2 antibodies [34?]. If,
indeed, IL-2 is a relevant limiting factor for the activity of
tumor-specific T cells, an interesting adjunct to existing
vaccines could be the recombinant adenovirus-IL-2 cur-
rently being investigated by direct injection into solid
Soluble factors produced by tumor or stromal cells could
induce a state of T-cell quiescence. TGF-b is widely
expressed and regulates T-cell homeostasis through mul-
tiple mechanisms. Its role in regulating anti-tumor T cells
has been documented in transgenic mice whose T cells
are insensitive to TGF-b signaling. These animals
resisted challenge to two types of tumors, with enhanced
Lymphocyte effector functions
Box 1 Possible reasons for the coexistence of tumor cells with
primed tumor-specific T cells.
- environment not permissive to T-cell infiltration
- decrease or loss of antigen expression
- resistance to lysis, or to TRAIL- or Fas-induced apoptosis
- contact inhibition of T cells (NK inhibitory receptors)
- shortage of soluble factors (tryptophan, arginine, IL-2, etc.)
- inappropriate co-stimulation
- immunosuppressive soluble factors (TGF-b, galectin-1, IL-10,
- Treg cells
- insufficient expansion of anti-tumor T cell clones
- T cell apoptosis within the tumor
Tumor resistance: when lymphocytes are competentex vivo.
Lymphocyte quiescence: when lymphocytes are
Too low lymphocyte:tumor cell ratio.
TRAIL, TNF-related apoptosis-inducing ligand.
Current Opinion in Immunology 2005, 17:320–325www.sciencedirect.com
CD8+-mediated tumor-specific CTL responses .
Another soluble factor that might be involved in T-cell
quiescence is the lectin galectin-1, which was reported to
inhibit the production of Th1 cytokines and to induce
apoptosis (reviewed in ). It was also shown to protect
murine melanoma cells from attack by T cells .
Regulatory T cells in lymphocyte quiescence
Regulatory T cells might play an important part in anti-
tumor lymphocyte quiescence. Wang and colleagues
[39??] demonstrated the existence of tumor-specific
human regulatory cells. They showed that anti-LAGE-
1 CD4+T-cell clones, derived from lymphocytes infil-
trating into a melanoma tumor, had potent suppressive
activities that were triggered by an antigenic peptide
presented on HLA-DR13. Both proliferation of and cyto-
kine secretion by autologous indicator CD4+clones were
strongly inhibited. This is the first description of a human
suppressive CD4+clone with a defined specificity. From
other recent papers, we note that Tregs were shown to be
recruited into ovarian tumors through CCL22 [40?].
There was also a twofold enrichment of Tregs in meta-
static melanoma lymph nodes in comparison to the pro-
portions found in tumor-free nodes or blood . Coming
is worth notingthat Tregs, which depend onIL-2 without
producing it themselves, compete for this growth factor
with responder T cells . In addition, they were also
shown to induce the expression of IDO by DCs, thereby
depleting tryptophan supplies [43?].
So far, the therapeutic vaccination of cancer patients with
defined tumor antigens has resulted in objective clinical
efficacy in only a minority of patients: some evidence of
tumor regression in about 20%, and clinical responses
assessed with RECIST criteria in about 3% [4,44].
In the majority of vaccinated patients who do not show
tumor regression, but who nevertheless have numerous
tumor-specific T cells, we need to better understand the
rules governing this coexistence. A promising approach to
address this is gene expression profiling, not only of the
tumor but also of anti-tumor T cells. One study has
managed to distinguish blood mononuclear cells obtained
from renal carcinoma patients from blood mononuclear
cells from normal donorsoreven patientswith other types
of cancer . Subtle and intriguing differences in gene
expression have been observed between circulating
CD8+T cells from melanoma patients and those from
healthy donors, and several of the discriminating genes
are related to apoptosis .
clarify thetumorrejection processinthefew patients who
benefit from vaccination. Such a study has already shown
that the simple model of rejection by numerous anti-
vaccine CTLs does not account for what happens in all
regressing tumors [16?]. Unforeseen effector mechanisms
might prove to be important; for example, IFN-g pro-
duced by murine CD8+T cells, which interferes with
tumor angiogenesis [47?,48].
There is still good reason to believe that such projects
may lead to more efficient, simple and non toxic proce-
dures for therapeutic vaccination against cancer.
We thank Ygierne Dodoo, David Mitchell and Pierre van der Bruggen for
their comments on the manuscript, and Suzanne Depelchin for editorial
assistance. Supported by grants from the Fonds National de la Recherche
Scientifique (to TC), Te ´le ´vie, the Fonds J Maisin, the Fondation Salus
Sanguinis, Fortis Banque Assurances and VIVA, and the Fe ´de ´ration belge
contre le Cancer.
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Current Opinion in Immunology 2005, 17:320–325