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,,§
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Laboratory of Molecular and Tumor Immunology, Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, OR 97213;
Department of Biochemistry and Molecular Biology, Oregon Graduate Institute, Portland, OR 97291; and
Oregon Cancer Center and
§
Department of Molecular Microbiology and Immunology, Oregon Health Sciences University, Portland, OR 97201
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResults and DiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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Female C57BL/6J mice were purchased from The Jackson Laboratory (Bar Harbor, ME). MHC II gene knockout (KO) mice (C57BL/6 Tac-[KO] Aß N5) and MHC I and II double KO mice were purchased from Taconic Farms (Germantown, NY). Recognized principles of laboratory animal care were followed (Guide for the Care and Use of Laboratory Animals, National Research Council, 1996), and all animal protocols were approved by the Earle A. Chiles Research Institute animal care and use committee. D5 is a poorly immunogenic subclone of the spontaneously arising B16BL6 tumor (22). D5-G6 is a stable murine GM-CSF-transduced D5 clone, which secretes GM-CSF at 400 ng/ml/106 cells/24 h (22). Both were provided by Dr. Suyu Shu, Cleveland Clinic Foundation (Cleveland, OH). MCA-101 is a chemically induced fibrosarcoma (gift from Dr. Nicholas Restifo, National Cancer Institute, National Institutes of Health) (23). Tumor cells were cultured in complete medium (CM), which consisted of RPMI 1640 (BioWhittaker, Walkersville, MD) containing 0.1 mM nonessential amino acids, 1 mM sodium pyruvate, 2 mM L-glutamine, and 50 µg/ml of gentamicin sulfate. This was further supplemented with 50 µM 2-ME (Aldrich, Milwaukee, WI), and 10% FBS (Life Technologies, Grand Island, NY). Tumor cells were harvested two or three times per week by brief trypsinization and were maintained in T-75 or T-150 culture flasks.
Adoptive immunotherapy
Vaccination was performed by injecting 1 x 106 D5-G6 tumor cells s.c. into both the fore and hind flanks of mice. Eight days later, inguinal and axillary LNs (D5-G6 TVDLN) were collected, and single-cell suspensions were prepared and cultured at 2 x 106 cells/ml of CM in 24-well plates with 50 µl of a 1/40 dilution of 2C11 ascites (anti-CD3). This dilution was determined previously to be optimal for T cell activation. After 2 days of activation, the T cells were harvested and subsequently expanded at 0.1 x 106 cells/ml in CM containing 60 IU/ml IL-2 (gift from Dr. Marty Giedlin, Chiron, Emeryville, CA) in Lifecell tissue culture flasks (Nexell Therapeutics, Irvine, CA) for 3 additional days. Effector T cells were then harvested and washed twice in HBSS, and graded numbers of effector T cells were injected i.v. into B6 mice with 3-day experimentally established D5 pulmonary metastases (five mice per group unless indicated otherwise). Pulmonary metastases were generated by tail vein injection of 0.1–0.2 x 106 tumor cells. Starting on the day of T cell infusion, mice received 90,000 IU of IL-2 i.p. once per day for 2 or 4 days. Animals were sacrificed 11–13 days following tumor inoculation by CO2 narcosis. Lungs were resected and fixed in Feketes solution. The number of pulmonary metastases was counted in a blinded fashion. Metastases that were too numerous to count accurately were assigned a value of 250. In some experiments effector T cells were transferred into mice depleted of T or NK cells either by sublethal irradiation (500 rad) 1 day before T cell transfer or by injection of anti-NK1.1 mAb (PK136). In some experiments T cells were transferred into tumor-bearing MHC II KO mice or MHC I and II double KO mice.
Monoclonal Ab-mediated depletion of NK cells or T cell subsets
In vivo depletion of CD4+ and CD8+ T cells was accomplished by treatment with mAbs produced by the GK1.5 (anti-CD4, American Type Culture Collection, Manassas, VA; TIB 207), 2.43 (anti-CD8, American Type Culture Collection, TIB 210), or PK136 (anti-NK1.1, American Type Culture Collection, HB-191) hybridomas, respectively. Vaccination was performed on day 0, and mice were given 50 µl of ascites (anti-CD4 or CD8) i.p. in 0.5 ml of HBSS 1 day before and 2 and 5 days after vaccination. This regimen effectively depleted either CD4+ or CD8+ T cells (data not shown) as determined by flow cytometric analysis with labeled anti-CD4 or CD8 mAb (PharMingen, San Diego, CA). Purified rat Ig (500 µg; I-4131, Sigma, St. Louis, MO) was used as control Ab. NK cell depletion was achieved by administration of 100 µl of PK136 hybridoma ascites i.p. 1 day before T cell transfer.
Flow cytometric analysis
Flow cytometry was performed on a FACScan (Becton Dickinson, Mountain View, CA), and data were analyzed with CellQuest software (Becton Dickinson). FITC- or PE-conjugated anti-CD4, CD8, NK1.1, I-Aß, and CD11c were purchased from PharMingen. FITC-conjugated OX-40 and Ly6-C Abs were prepared in our laboratory with purified Ly6.2-C Ab (from culture supernatant of hybridoma 143-4-2, American Type Culture Collection, CRL-1970) and OX86 Ab (gift from Dr. Andrew W. Weinberg). Purified anti-CD16/CD32 mAb was prepared from culture supernatant of the 2.4G2 hybridoma (American Type Culture Collection) and used to block nonspecific binding to Fc receptors.
Cytotoxicity assays
Six-hour 51Cr release assays were used to
detect tumor-specific cytotoxicity of effector T cells. Tumor targets,
including D5, D5 treated with IFN-
, and MCA-101, were labeled with
Na251CrO4
(New England Nuclear, Boston, MA), washed, and incubated with effector
T cells as previously described (24). D5 tumor cells were
incubated overnight with 5 ng/ml recombinant IFN- to up-regulate MHC
class I expression. Standard 3-day lymphokine-activated killer (LAK)
cells, generated by culturing splenocytes with 6000 IU/ml IL-2 for 3
days, were used as a positive control for tumor cell lysis in all
experiments.
Survival and tumor challenge experiments
Mice bearing 3-day pulmonary metastases were treated with effector T cells generated as described above, but instead of being sacrificed to count pulmonary metastases, they were observed for overall survival. Mice were sacrificed when they became cachectic or moribund. To determine whether surviving mice were immune, they were rechallenged s.c. with 2 x 104 D5 tumor cells (10 x TD100) 50 or 150 days after adoptive immunotherapy. In some experiments mice were depleted of either CD4 or CD8 subsets by injection of 50 µl of ascites (anti-CD4 or CD8) i.p. in 0.5 ml of HBSS 1 day before and 2 and 5 days after rechallenge with D5 tumor cells. The incidence of tumor formation and tumor growth were assessed every other day. Age-matched naive mice served as controls. The significance of differences in survival time between the two experimental groups was determined by Kaplan-Meier analyses and log rank tests.
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Results and Discussion |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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It is now well accepted that antitumor immunity is initiated by
the acquisition of tumor-associated Ags by APCs and their subsequent
presentation to immunocompetent T cells. Dendritic cells are thought to
be the key APC responsible for cross-priming the immune response to
many different Ags (25, 26). CTL priming by a GM-CSF
gene-modified tumor vaccine also occurs via a cross-priming pathway
(27, 28). To examine whether local secretion of GM-CSF
increased the number of dendritic cells available for cross-priming an
antitumor immune responses in TVDLN, we stained the cells from lymph
nodes draining either unmodified D5 tumor or GM-CSF-producing D5-G6
tumor with anti-CD11c and anti-MHC II I-Aß, two markers of
dendritic cells. Naive LN and TVDLN of D5-vaccinated mice contained
similar numbers of dendritic cells (1.4 and 1.6%), whereas TVDLN of
D5-G6-vaccinated mice exhibited a 3-fold increase in the number of
double-positive DCs (4.8%; Fig. 1
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The activation status of freshly isolated TVDLN T cells 8 days
following vaccination was assessed by flow cytometry. Expressions of
OX40 and Ly6-C were used as markers for the number of activated CD4 and
CD8 T cells, respectively (29, 30). Vaccination with D5-G6
increased the percentage of
OX40+CD4+ T cells to 11.2%
compared with 4.4% for D5 TVDLN or 3.9% for naive LN
CD4+ T cells (Fig. 2). A similar pattern was seen for
Ly6-C+CD8+ expression. In
naive LNC 28.6% of CD8+ T cells expressed
Ly6-C+. D5-G6 TVDLN had a 16.4% increase (from
28.6 to 45.0%) in
Ly6-C+CD8+ T cells compared
with a 6% increase (from 28.6 to 34.6%) for
CD8+ T cells from D5 TVDLN (Fig. 2). Thus, there
is an increased number of activated CD4+ and
CD8+ T cells in D5-G6 TVDLN, consistent with the
hypothesis that the increased number of DCs are priming more T cells to
tumor-associated Ags.
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A major contribution of CD4+ T cells to the
cross-priming of CD8+ CTL occurs via the
activation of dendritic cells by CD40/CD40L cross-linking (8, 31, 32, 33). CD4+ T cell help can also be
replaced by injecting mice with an anti-CD40 mAb that engages CD40
on dendritic cells, a signal that is normally provided by CD40L on
activated CD4+ T cells (32, 33).
However, some CTL responses to viral Ags develop independently of
CD4+ T cell help (34). In this case,
direct activation of CTL is mediated by dendritic cells, which,
secondary to viral infection, have acquired costimulatory properties in
the absence of the cross-linking of CD40 (31). To address
directly the requirement for CD4+ T cell help in
the priming of tumor-specific CD8+ T cells, we
attempted to generate effector T cells from MHC II KO mice. These mice
lack MHC class II-restricted CD4+ T cells and
fail to prime CTL responses efficiently (32, 33). As shown
in Table I, the adoptive transfer of effector T cells generated from
MHC II KO mice vaccinated with D5-G6 mediated regression of pulmonary
metastases at both high (70 x 106 cells)
and low doses (35 x 106 cells) of T cells
transferred. This shows that both the priming and subsequent generation
of therapeutic CD8+ T cells could be accomplished
in the absence of MHC class II-restricted CD4+ Th
cells by vaccination with the GM-CSF-secreting tumor, D5-G6. While MHC
class II-restricted CD4+ T cells are eliminated
in MHC II KO mice, a minor population of CD4+ T
cells, many of them restricted by CD1 molecules, have been found in
these mice (35). Recent studies have shown that these
CD1-restricted CD4+ T cells can provide help for
CTL against Toxoplasma gondii or for Ab responses to
GPI-linked proteins of Plasmodium and Trypanosoma
(36). To determine whether this subpopulation of T cells
may provide T cell help in the generation of an antitumor immune
response in MHC II KO mice, MHC II KO mice were depleted of
CD4+ T cells by Ab administration before and
after D5-G6 vaccination. Flow cytometric analysis confirmed the
depletion (from 4.0 to 0.2%) of this minor population (data not
shown). Effector T cells generated from CD4-depleted mice were highly
therapeutic; complete regression of pulmonary metastases was observed
with depletion of minor population of CD4+ T
cells (Table I).
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To generate both CD4+ and
CD8+ effector T cells independently, C57BL/6
wild-type (wt) mice were depleted of CD4+ or
CD8+ T cells by Ab administration before and
following D5-G6 vaccination. Flow cytometric analysis of TVDLN obtained
from anti-CD4 or anti-CD8-treated mice confirmed the depletion
of these subsets (data not shown). Effector T cells generated from
nondepleted, CD4-depleted, and CD8-depleted wt mice were then
adoptively transferred into mice with established pulmonary metastases.
To generate effector T cells from D5-G6 TVDLN, we routinely activated
LN cells with anti-CD3 Ab for 48 h and then expanded the
activated T cells in CM with low dose IL-2 (60 IU/ml). Previously we
have shown that in vitro activated effector T cells generated from
D5-G6-vaccinated mice are tumor specific, as evidenced by
tumor-specific IFN- release and tumor-specific cytotoxicity
(37). To determine the cytolytic activity of
effector T cells generated from CD4-depleted mice, short term
51Cr release assays were performed. Target cells
included D5 (very low level of MHC I expression), D5 treated in vitro
with recombinant IFN- to up-regulate MHC I expression (D5/IFN-),
and a syngeneic fibrosarcoma, MCA-101. LAK cells were used to prove
that targets could be lysed. Both D5 and MCA 101 tumor cells were lysed
equally by LAK cells; however, LAK-mediated lysis of IFN--treated D5
was reduced (Fig. 3A). We
frequently observe this pattern of reduced susceptibility to LAK
killing when MHC class I has been up-regulated by IFN-. The effector
T cells generated from TVDLN in D5-G6-vaccinated mice exhibited a low
level D5-specific lysis, which became more detectable if D5 cells were
pretreated with IFN- (Fig. 3B). As expected,
CD8+ effector T cells (Fig. 3C), but
not CD4+ effector T cells (Fig. 3D),
were highly cytolytic.
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). In contrast, effector T cells
from CD8-depleted mice were ineffective at both the high and low doses
of T cells transferred (Table II). Consistent with our findings that
class II-restricted CD4+ T cells were not
required to generate therapeutic T cells in the MHC II KO mice,
depletion of CD4+ T cells by mAb treatment did
not eliminate the priming of tumor-specific CTL or therapeutic
CD8+ effector T cells. This suggests that neither
the class II-restricted CD4+ T cells nor the
non-MHC II-restricted CD4+ NKT cells are required
for efficient priming of CD8+ T cells.
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To ensure that the observed antitumor effects were directly
mediated by the adoptively transferred T cells, we had to exclude
indirect mechanisms mediated via host T or NK cells. First we
transferred effector T cells into tumor-bearing mice ablated of
lymphocytes by a sublethal dose of irradiation. While all irradiated
control mice treated with IL-2 alone developed >250 pulmonary
metastases, complete tumor regression was observed in irradiated mice
that received both IL-2 and effector T cells (Table III). Complete eradication of pulmonary
metastases was also seen in tumor-bearing mice depleted of NK cells by
injection of anti-NK1.1 Ab (PK136; Table III). Depletion of NK
cells by anti-NK1.1 Ab was confirmed by flow cytometric analysis
and by elimination of LAK activity as determined by in vitro assays
with cells obtained from treated mice (data not shown). Because
irradiation did not completely eliminate all T cells, adoptive
immunotherapy was also performed in either CD4-deficient MHC II KO or
CD4 and CD8-deficient MHC I and II KO tumor-bearing mice. Again,
significant (p < 0.05) tumor regression
occurred in these mice as well. These results clearly indicate that
effector T cells can mediate regression of pulmonary metastases without
the participation of host T cells or NK cells.
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To determine whether adoptive immunotherapy with
CD8+ effector T cells improved survival, mice
bearing 3-day established pulmonary metastases received
CD8+ T cells and were observed for survival after
adoptive T cell therapy (Fig. 4). In
experiment 1, 8 of 9 (89%) mice receiving 70 x
106 effector T cells survived for >100 days. The
one mouse that died did so 21 days after the death of the last control
mouse, which received no T cells. In experiment 2, all mice receiving
35 x 106 effector T cells survived >100
days, while all control mice that received only IL-2 therapy died
before day 25. In the third experiment, 30 of 30 mice that received
35 x 106 effector T cells generated from
CD4-depleted mice survived at least 50 days. Thus, effector T cells
from D5-G6-vaccinated CD4-depleted mice not only decreased the number
of pulmonary metastases, but apparently cured the majority of mice
treated.
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Our results suggest that CD4+ T cells do not
play a critical role during either the priming phase or the acute
effector phase (as measured by the reduction in pulmonary metastases)
in this adoptive immunotherapy model. To examine whether
CD8+ effector T cells can cure mice of systemic
tumor without CD4+ T cell help, wt
CD8+ T cells were adoptively transferred into MHC
II KO mice bearing established pulmonary metastases (Fig. 5). Both wt and MHC II KO mice treated
with IL-2 alone were dead before day 25. The adoptively transferred
CD8+ T cells were highly therapeutic as all wt
mice receiving effector T cells survived >80 days. However, while MHC
II KO mice treated with wt CD8+ T cells survived
longer than MHC II KO mice treated with IL-2 alone
(p < 0.05), they all died before day 70. These
MHC II KO mice succumbed to solitary metastases that developed at
various anatomic sites (lung, face, hip, and tail). Thus, when only
CD8+ effector T cells are adoptively transferred,
host CD4+ T cells appear to be critical for
either maintaining effector function of CD8+ T
cells or for activation of other host effector mechanisms that are not
required for acute tumor regression in the lung, but are important for
complete eradication of residual tumor.
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To test whether immunological memory developed in the wt mice
cured of systemic tumor by the adoptive transfer of CD4-depleted
effector T cells, mice surviving >120 days were subsequently
rechallenged with D5 tumor cells. While all naive mice rapidly
developed tumor nodules and had to be sacrificed, all eight mice in
experiment 1 and three of five mice in experiment 2 were resistant to a
subsequent tumor challenge. The two mice in experiment 2 that developed
tumor did so much later than the control naive mice that were injected
with the same number of tumor cells (Fig. 6). Thus, the adoptive transfer of
effector T cells from CD4-depleted mice cured the majority of mice and
led to the development of long term protective immunity in 11 of
13 mice.
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Our data clearly show that when vaccination is performed with this
GM-CSF-secreting tumor vaccine, neither priming nor the acute effector
function of CD8+ T cells requires
CD4+ T cell help. However, the requirement for
host CD4+ T cells to cure and develop and/or
maintain a protective antitumor CD8+ memory
response and the mechanism responsible for this effect need further
characterization. Others have reported divergent requirements for
CD4+ T cell help depending on the Ag studied and
the experimental design. The long term H-Y-specific CTL memory response
is independent of CD4+ T cells (38),
although it is generally accepted that CD4+ T
cells are important for maintaining a long term CTL response against
viral Ags and for the clearance of chronic viral infections (39, 40). While our results clearly demonstrated that
CD4+ T cells are not critical for priming or
effector function immediately following adoptive transfer, we
considered it likely that they would be required to maintain a
protective antitumor memory response given our results with the MHC II
KO mice. To address the role of CD4+ T cells in
maintaining the antitumor memory response, we depleted either
CD4+ or CD8+ T cells from
mice cured by the adoptive transfer of therapeutic
CD8+ effector T cells. These mice had survived
either 50 days (short term memory) or >150 days (long term memory) and
appeared to be tumor free at the time of mAb treatment. These two
groups of mice were then challenged with D5 tumor cells and monitored
for tumor growth. Mice that had survived 50 days (short term memory)
when they were treated with rat IgG or anti-CD4 were resistant to
the tumor challenge, but all mice depleted of
CD8+ T cells succumbed to tumor growth
(p < 0.05; Fig. 7A). Interestingly, at 150
days following adoptive transfer (long term memory) the majority of
CD8-depleted and CD4-depleted mice, but not the control rat Ig-treated
mice, developed tumor after the tumor challenge (Fig. 7B).
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Depigmentation in mice that survived a tumor challenge
Five of 14 mice that were cured by adoptive immunotherapy with
CD8+ effector T cells and survived a secondary
challenge of D5 tumor developed various degrees of depigmentation. This
started around day 80 after adoptive immunotherapy and ranged from
randomly distributed small white patches to a few large spots that
continued to progress over time. One mouse with several large areas of
depigmentation is shown in Fig. 8. A
naive untreated mouse is shown for comparison.
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In the B16 mouse melanoma model, depigmentation can be induced by
passive transfer of anti-TRP-1 mAb (42) or active
immunization with either insect-derived TRP-1 protein
(44), a plasmid DNA containing xenogenic TRP-1 cDNA
(45), or a recombinant mouse TRP-2 vaccinia virus
(46). Interestingly, mechanisms required for tumor
protection induced by TRP-1 DNA vaccination were different from those
required for depigmentation (45). Tumor rejection, but not
depigmentation, required CD4+ T cells,
NK1.1+ cells, and the Fc receptor -chain..
Using the same homologous DNA vaccination approach, Bowne et al. were
also able to induce tumor immunity by DNA immunization against human
TRP-2, but not by immunization with the syngeneic gene
(47). Immunization against human TRP-2 induced both
autoantibodies and autoreactive cytotoxic T cells. In this case both
tumor immunity and depigmentation required CD8+ T
cells, but not Abs. Interestingly, only depigmentation required
perforin; tumor immunity proceeded in the absence of perforin. Thus,
autoimmunity induced against two closely related autoantigens, TRP-1
and TRP-2, involved different mechanisms, i.e., Ab vs a
CD8+ T cell response (47). Using
vaccinia viruses immunization strategies, Overwijk et al. were able to
demonstrate a striking depigmentation and melanocyte destruction in
mice vaccinated with murine TRP-1, but not vectors containing other
melanocyte differentiation Ags (TRP-2, MART-1, or gp100)
(46). These mice also rejected a lethal challenge of B16
melanoma, indicating that the immune response against TRP-1 could
destroy both normal and malignant melanocytes. CTL specific for TRP-1
could not be detected in depigmented mice, but high titers of
anti-TRP-1 IgG Abs were present, further supporting the hypothesis
that different mechanisms (humoral or cellular) can mediate both
autoimmunity and antitumor immunity.
To our knowledge, the results presented in this study are the first direct evidence that adoptive transfer of CD8+ T cells alone could induce depigmentation. In agreement with Bowne et al., (47), we observed that while effector T cells generated from D5-G6-vaccinated wt or perforin knockout mice can cure animals of systemic tumor, only wt effector T cells induce depigmentation (37) (W. Hauke, H.-M. Hu, and B. A. Fox, manuscript in preparation). The CD8+ effector T cells used for adoptive immunotherapy were found to recognize the H-2 Kb-restricted dominant TRP-2 peptide (48) and three mouse gp100 peptides (H.-M. Hu et al., manuscript in preparation), but not the TRP-1 peptide described by Dyall and colleagues (49). Using an ELISA with immobilized proteins from a solubilized melanosome fraction prepared from D5 tumor, we were also able to detect a strong anti-melanosome Ab response in long term surviving mice regardless of whether they developed depigmentation (data not shown). Current studies are investigating the possible contributions of both CD4 Th cells and humoral immunity to the protective antitumor memory response observed in mice cured by adoptive immunotherapy.
Although it remains to be determined whether our observations from the D5 model will extend to other tumor models, elucidation of the mechanism for CD4-independent priming of therapeutic CD8+ T cells will probably yield information critical to the design of therapeutic vaccine and adoptive immunotherapy strategies.
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Acknowledgments |
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Footnotes |
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2 Current address: Department of Surgery, Ludwig Maximilians Universität München, Klinikum Grosshadern, Marchioninistrasse 15, 81377 Munich, Germany.
3 Address correspondence and reprint requests to Dr. Bernard A. Fox, Laboratory of Molecular and Tumor Immunology, Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, OR 97213.
4 Abbreviations used in this paper: TVDLN, tumor vaccine draining lymph node; LN, lymph node; KO, knockout; wt, wild type; LAK, lymphokine-activated killer cells; D5-G6, a GM-CSF-producing clone of B16BL6; CM, complete medium; TRP, tyrosinase-related protein; AIT, adoptive immunotherapy.
Received for publication August 18, 2000. Accepted for publication July 24, 2000.
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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M. J. Dobrzanski, J. B. Reome, J. A. Hollenbaugh, J. C. Hylind, and R. W. Dutton Effector Cell-Derived Lymphotoxin {alpha} and Fas Ligand, but not Perforin, Promote Tc1 and Tc2 Effector Cell-Mediated Tumor Therapy in Established Pulmonary Metastases Cancer Res., January 1, 2004; 64(1): 406 - 414. [Abstract] [Full Text] [PDF]
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C. H. Poehlein, H.-M. Hu, J. Yamada, I. Assmann, W. G. Alvord, W. J. Urba, and B. A. Fox TNF Plays an Essential Role in Tumor Regression after Adoptive Transfer of Perforin/IFN-{gamma} Double Knockout Effector T Cells J. Immunol., February 15, 2003; 170(4): 2004 - 2013. [Abstract] [Full Text] [PDF]
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F. G. Gao, V. Khammanivong, W. J. Liu, G. R. Leggatt, I. H. Frazer, and G. J. P. Fernando Antigen-specific CD4+ T-Cell Help Is Required to Activate a Memory CD8+ T Cell to a Fully Functional Tumor Killer Cell Cancer Res., November 15, 2002; 62(22): 6438 - 6441. [Abstract] [Full Text] [PDF]
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H.-M. Hu, H. Winter, J. Ma, M. Croft, W. J. Urba, and B. A. Fox CD28, TNF Receptor, and IL-12 Are Critical for CD4-Independent Cross-Priming of Therapeutic Antitumor CD8+ T Cells J. Immunol., November 1, 2002; 169(9): 4897 - 4904. [Abstract] [Full Text] [PDF]
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H.-M. Hu, C. H. Poehlein, W. J. Urba, and B. A. Fox Development of Antitumor Immune Responses in Reconstituted Lymphopenic Hosts Cancer Res., July 15, 2002; 62(14): 3914 - 3919. [Abstract] [Full Text] [PDF]
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A. Ribas, L. H. Butterfield, S. N. Amarnani, V. B. Dissette, D. Kim, W. S. Meng, G. A. Miranda, H.-J. Wang, W. H. McBride, J. A. Glaspy, et al. CD40 Cross-Linking Bypasses the Absolute Requirement for CD4 T Cells during Immunization with Melanoma Antigen Gene-modified Dendritic Cells Cancer Res., December 1, 2001; 61(24): 8787 - 8793. [Abstract] [Full Text] [PDF]
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M. P. Velders, S. McElhiney, M. C. Cassetti, G. L. Eiben, T. Higgins, G. R. Kovacs, A. G. Elmishad, W. M. Kast, and L. R. Smith Eradication of Established Tumors by Vaccination with Venezuelan Equine Encephalitis Virus Replicon Particles Delivering Human Papillomavirus 16 E7 RNA Cancer Res., November 1, 2001; 61(21): 7861 - 7867. [Abstract] [Full Text] [PDF]
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H. Winter, H.-M. Hu, K. McClain, W. J. Urba, and B. A. Fox Immunotherapy of Melanoma: A Dichotomy in the Requirement for IFN-{{gamma}} in Vaccine-Induced Antitumor Immunity Versus Adoptive Immunotherapy J. Immunol., June 15, 2001; 166(12): 7370 - 7380. [Abstract] [Full Text] [PDF]
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