| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Department of Pathology and Comprehensive Cancer Center, Ohio State University Medical Center, Columbus, OH 43210
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Identification of B7-1 and B7-2 as the prototypic costimulatory molecules has led to novel approaches to tumor immunotherapy (11, 12, 13, 14, 15). Although expression of these molecules on tumors often leads to the rejection of tumor cells by CD8 T cells (11, 13, 14), the mechanism for the effect is less clear. Based on the fact that costimulation promotes T cell clonal expansion, it has been suggested that B7-1 and B7-2 promote tumor rejection by enhancing the induction of antitumor T cell response (3). However, because the induction of CTL response can be mediated by host APC (3, 16, 17, 18), it is unlikely that expression of B7-1 and B7-2 on the tumors would be essential for clonal expansion of tumor-specific T cells. In this regard, we and others have suggested that B7-1 expressed on tumor cells promotes the effector function of CTL, including both autoreactive and tumor-reactive CTL (14, 19, 20, 21). A critical role for B7-1 at the effector phase may provide an opportunity to reinvigorate antitumor CTL. In this study, we used an adoptive transfer model to analyze the function of B7-1 on the tumor cells at the effector phase. Our results demonstrate that tumor-specific CTL preferentially eliminated B7-1+ tumor cells even when the B7-1+ and B7-1- were administered as a mixture and formed microchimerism in vivo. Remarkably, either expression of B7-1 on the tumor cells or local administration of a mAb specific for CD28 substantially increased the susceptibility of large tumors to tumor-specific T cells and led to a substantial clinical benefit to the host.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Transgenic mice expressing TCR specific for tumor Ag P1A35-43:Ld complex have been described (9). The TCR transgenes were backcrossed with BALB/cByJ for at least seven generations before they were used for this study. BALB/c mice with the targeted mutation of the RAG-2 gene were purchased from Taconic Farms (Germantown, NY).
Cell lines
Plasmacytoma J558 (BALB/c origin) transfected with either vector alone (J558-Neo) or wild-type B7-1 (J558-B7) has been described (14). B7+ and B7- P815 (DBA/2 origin) and Meth A (BALB/c origin) tumor cells were provided by Dr. L. Chen (Mayo Clinic, Rochester, MN) and have been described (22).
Abs and flow cytometry
Ascites of anti-CD28 mAb 37N (23) and
anti-CTLA4 mAb 4F10 (24) were produced using
hybridomas kindly provided by Drs. J. P. Allison (University of
California, Berkeley, CA) and J. A. Bluestone (University of Chicago,
Chicago, IL), respectively. Cell surface expression of B7-1 or
Ld was detected using biotinylated anti-B7-1
mAb 10.16A or anti-Ld mAb HB-27 (BD
PharMingen, San Diego, CA); cell surface-bound mAb was detected using
PE-streptavidin. Abs against cell surface molecules such as V
8 (PE),
CD8 (CyChrome), CD62L (PE), CD43 (FITC, 1B11), and CD44 (FITC) were
purchased from BD PharMingen.
Adoptive transfer of purified transgenic T cells
Pools of spleen and lymph node cells from the P1CTL-transgenic mice were incubated with a mixture of mAbs (anti-CD4 mAb GK1.5, anti-FcR mAb 2.4G2, anti-CD11c mAb N418); after removal of unbound mAbs, the cells were incubated with anti-Ig-coated magnetic beads. The Ab-coated cells were removed by a magnet. The unbound cells consisted of >90% CD8 T cells, with no detectable CD4 T cells. The purified T cells were adoptively transferred into RAG-2-/- mice that either had established tumors or had received tumor cells at the same day of adoptive transfer. In some experiments, the P1CTL were activated for 4 days with their cognate peptide (P1A35–43, 0.1 µg/ml) in vitro before adoptive transfer.
Tumorigenicity assay
Given numbers of tumor cells were injected in the flanks of mice as described (14). The tumor size and incidence were determined by physical examination every other day after tumor inoculation.
Immunohistochemistry with anti-B7-1 mAb
Frozen sections of tumors were fixed with acetone and incubated with anti-B7-1 mAb 10.16A hybridoma (25) supernatants. After extensive washes, the anti-B7-1 mAb was detected by biotinylated goat anti-hamster Abs followed by HPR-conjugated streptavidin.
RNase protection assay
Total RNAs from spleens or tumor-infiltrating cells were
isolated with Trizol reagent (Life Technologies, Gaithersburg, MD). The
concentration of RNA in each sample was assessed
spectrophotometrically. The multiprobe RNase protection assay kit
(RiboQuant; BD PharMingen) was used, with the assay performed according
to the manufacturer’s protocol. Briefly, a set of
32P-labeled RNA probes synthesized from DNA templates using
T7 polymerase was hybridized with 5 µg total RNA, after which free
probes and other single-stranded RNA were digested with RNases. The
remaining RNase-protected probes were purified and then resolved on
denaturing polyacrylamide gels. The following template sets for murine
apoptosis and cytokines were used in the present study:
mAPO2: bcl-W, bfl-1, bcl-X, bak, bax, bcl-2, bad,
L32, and GAPDH; mCK-3b: TNF-
, LT, TNF-, IL-6, IFN-
,
IFN-, TGF-1, TGF-2, TGF-3, macrophage migration inhibiting
factor (MIF), L32, and GAPDH.
Cytotoxicity assay
As the effectors, we used ex vivo spleen cells after a short term (12 h) reactivation in vitro with the P1A peptide (0.1 µg/ml). Data were presented as percent specific lysis. P338D1 cells, pulsed with tumor antigenic peptide P1A or a control Ld-binding viral peptide, were used as the targets.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
To test whether P1CTL preferentially reject
B7-1+ tumor cells, we injected J558-B7 and
J558-Neo tumor cells at separate flanks of the same
RAG-2-/- mice. Some of the tumor-bearing mice
were then adoptively transferred with purified CD8 T cells from P1CTL
transgenic mice. As shown in Fig. 1
, top, J558-Neo and J558-B7 grew at comparable rates in
RAG-2-/- mice that received no T cells. In mice
that received P1CTL, J558-B7 tumors either failed to develop (Fig. 1A) or developed in one of the mice and rapidly rejected
(Fig. 1B). In contrast, J558-Neo tumors grew progressively
even when large numbers of P1CTL were transferred, although the tumor
growth was delayed by 1 or 2 wk, and the mice survived up to 1 mo
longer than did the groups that received no T cells. Thus, P1CTL
preferentially rejected the B7-1+ tumor cells.
The ability of P1CTL to reject the B7-1+ tumors
and to retard the development of the J558-Neo tumors demonstrates that
CD8 T cells specific for a single peptide can reject tumors without
participation of any other Ag-specific lymphocytes.
|
A, left column).
As shown in Fig. 1
, of the mice that rejected the
B7-1+ tumors, some never developed tumors,
whereas others developed and rejected the tumors. As expected, P1CTL
from those mice that had transient tumor growth displayed a higher
level of CD44 and had a higher proportion of
CD62Llow cells. Moreover, the number of cells
with an effector cell marker (26) (1B11, the 130-kDa form
of CD43) was also higher. In the group of mice that never developed
tumors, however, T cells had a partial activation phenotype. After a
short term in vitro restimulation, spleen cells harvested from all
recipient mice developed P1A-specific cytotoxicity, although T cells
from mice with transient tumor growth were somewhat more cytotoxic.
|
).
However, in mice that received P1CTL, significant tumor retardation was
observed. In two separate experiments involving different numbers of
P1CTL, we observed significant retardation in both the onset and growth
kinetics of tumors. Nevertheless, the majority of the mice did
eventually develop tumors, and the tumors did progress, albeit at a
reduced rate, until euthanasia became necessary.
|
, flow cytometry revealed
that tumor cells isolated from all J558-Neo tumor cells were
B7-1-, and all J558-B7 tumor cells were
B7-1+, as expected. In control mice that were not
treated by P1CTL, there was a slight dominance of the
B7-1+ tumor cells. Thus, expression of B7-1 on
the tumor cells did not hinder their growth in the absence of T cells.
In mice that received P1CTL, however, essentially all the surviving
tumor cells were B7-1-. Immunohistochemistry
revealed good microchimerism between the B7-1+
and B7-1- tumor cells in untreated mice.
However, in the P1CTL-treated mice, all but a few surviving tumor cells
expressed B7-1 molecules in vivo. These B7-1+
cells were not found in the single-cell suspension prepared from the
same sample, perhaps because they were being destroyed in vivo. The
fact that many of the B7-1- tumor cells were not
eliminated despite their proximity to the B7-1+
tumor cells indicates that B7-mediated enhancement of tumor destruction
in vivo is highly localized.
|
, in wild-type mice,
B7-1+ but not the B7-1-
P815 and Meth A tumors are rejected when they are injected separately
in the same mouse. When the two types of tumor cells were injected as a
mixture, all recipient mice developed tumors. To determine the cellular
origin of the tumor cells, the tumor cells were isolated ex vivo and
analyzed for their cell surface expression of B7-1 by flow cytometry.
The results indicated that all the tumor cells that had survived in
vivo were B7-1-. Thus, introduction of
B7-1+ tumor cells in the vicinity of
B7-1- tumor cells did not convey full protection
to their B7-1- tumor cells. Taken together, our
data indicate that cognate destruction of multiple lineages of
P1A-expressing tumors depends on B7-1 expressed on the tumor cells.
|
Our data, presented in the above section, indicate that expressing
costimulatory molecules on the tumor cells can enhance the effector
function of T cells in vivo. The most difficult obstacle for T cell
therapy is the resistance of large tumors to T cell treatment. To test
whether expression of B7-1 on the large tumors makes them more
susceptible to CTL-mediated tumor therapy, we injected either J558-Neo
or J558-B7 tumors into the RAG-2-/- mice. When
the tumors reached 1.1–1.5 cm, we injected 10 x
106 P1CTL i.v. into the tumor-bearing mice. As
shown in Fig. 5A, administration of transgenic P1CTL
resulted in a significant improvement in the survival of tumor-bearing
mice. Thus, untreated mice became moribund within a week after
the treatment had started in other groups, while all but one in each
group of treated mice survived >4 wk after treatment. However, 60% of
mice bearing J558-B7 tumors survived >12 wk; all mice with the
J558-Neo tumors succumb within this period (Fig. 5A). The treatment did not
eliminate the J558-B7 tumors, given that the tumor recurred in all mice
(data not shown). Although the mice with recurrent J558-B7 tumors
remained healthy at 12 wk after tumor cell injections, the tumor
burdens had made euthanasia necessary. These results indicated that
whereas the P1CTL are of some therapeutic value for vector-transfected
tumors, expression of B7-1 on the tumor cells made the large tumors
substantially more susceptible to CTL therapy.
|
1.0–1.5 cm in diameter; then 5 x 106
purified P1CTL were injected into each mouse i.v. As shown in Fig. 5B, the J558-B7 tumors were rapidly destroyed in all four
mice within 10 days after T cell adoptive transfer. Although all of the
J558-Neo tumors remained substantially viable, areas of scars and
tissue death were found in the J558-Neo tumors (Fig. 5C,
top). This result demonstrated that some immune rejection
was also under way in the J558-Neo tumors. We also examined the effect
of immunotherapy by H&E staining of tumor tissues. As shown in Fig. 5C, in the mice that received P1CTL, no viable cells were
observed throughout the sections of all four tumors. Although
substantial cell death was also observed in all of the J558-Neo tumor
sections, each of the tumors still consisted of a large number of
viable tumor cells. These results revealed at the cellular level that
large J558-B7 tumors are more susceptible to the P1CTL than were the
J558-Neo tumors in the same mice. Preferential rejection of the J558-B7
tumors over the J558-Neo tumors in the same mice clearly demonstrated
that local expression of B7-1 increased tumor susceptibility to CTL
therapy.
An issue of critical importance for tumor immunotherapy is whether the
requirement for local costimulation can be bypassed by in vitro
activation of tumor-specific T cells. To address this issue, we
adoptively transferred preactivated P1CTL to mice with J588-Neo and
J558-B7 tumors 1.0–1.5 cm in diameter. The activated P1CTL T cells
had strong cytotoxicity against P1A-peptide-pulsed targets (Fig. 6A). Despite the strong
cytotoxicity, they still showed preference in rejecting the
B7-1+ tumors. Thus, the J558-B7 tumors started to
shrink at 3 days after T cell therapy, and the tumors remained small
at the time when the mice had to be sacrificed due to the large size of
the J558-Neo tumors. The response of J558-Neo tumors was both delayed
and transient (Fig. 6B). Thus, preactivation of
tumor-specific T cells was insufficient to bypass the requirement for
local costimulation by B7-1.
|
A, genes involved in
regulation of apoptotic cell death were expressed at essentially the
same levels among T cells isolated from mice with the J558-B7 and
J558-Neo tumors, regardless of whether spleen cells or
tumor-infiltrating lymphocytes
(TIL)3 was used. Similarly,
expressions of TNF-, IL-6, IFN-, and TGF-1 among the spleen T
cells of mice bearing either J558-B7 or J558-Neo tumors were
comparable. In contrast, TIL from J558-B7 tumors expressed
substantially more IFN- mRNA (Fig. 7B). The enhanced
IFN- expression indicated that B7-1 on the tumor cells provided
local costimulation for P1CTL.
|
The data in B7-1 on the tumor cells conveys susceptibility
of large tumors to CTL therapy demonstrate that local
costimulation promotes CTL-mediated rejection of large tumors. Although
it is practically impossible to express B7-1 on all tumor cells,
B7-1-mediated signaling can potentially be achieved by using mAbs
specific for the B7 receptors, CD28 and CTLA4 (29, 30). We
therefore tested the effects of intratumor injection of anti-CD28
Ab 37N and anti-CTLA4 Ab 4F10 on P1CTL-mediated adoptive therapy of
tumor. J558-Neo tumor cells were injected into the
RAG-2-/- BALB/c mice that were left untreated
until the tumors reached diameters of 1–1.5 cm (Fig. 8). At this point, the mice received
5 x 106 purified
CD8+ P1CTL transgenic T cells i.v. On days 0
and 16 of T cell transfer, we injected control hamster Ig,
anti-CD28 mAb 37N, or anti-CTLA4 mAb 4F10 into the tumor cells
and monitored the growth of the tumors. As shown in Fig. 8, tumor
growth was comparable in the groups that received either control IgG or
anti-CTLA4 mAb 4F10. However, anti-CD28 mAb 37N substantially
prolonged the regression of the J558-Neo tumors. These results suggest
that the effector function of B7-1 can be achieved by local
administration with anti-CD28 mAb.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Numerous studies have documented that expression of B7-1 on the tumors enhances tumor rejection (11, 13, 14, 31). The mechanisms for this important function have not been clearly elucidated. It was originally suggested that B7 enhance antitumor CTL response by solely promoted priming of tumor-specific T cells. Although the role for B7-1 in promoting T cell priming has been clearly demonstrated (11, 27, 32, 33), it is unlikely that this is the only mechanism in that T cell priming can take place without direct stimulation by tumor cells. We and others have shown that B7-1 can play an important function for the effector function of antitumor and autoreactive T cells (14, 19, 21). In a model that involved a single clone of T cells, here we show that transgenic CTL specific for tumor Ag P1A preferentially rejected B7-1+ tumor cells when B7-1+ and B7-1- tumor cells were injected into the same RAG-2-/- mice. Because this study involved transgenic T cells specific for a single P1A peptide and multiple lineages of P1A-expressing tumors, it offered the strongest in vivo evidence to date for the notion that local costimulation can enhance the effector function of antitumor CTL (9, 14, 19, 21).
Two interesting issues remain to be resolved. First, what is the
mechanism for B7-1 to enhance effector function of tumor-specific T
cells? We showed that B7-1 enhanced cytolysis of J558-cells. Although
this can explain the increased rejection of J558-B7 tumors, it cannot
explain the preferential rejection of P815-B7 and Meth A-B7, because
the two lines are no more sensitive than their parental
B7-1- tumors (data not shown). As an alternative
hypothesis, Wu et al. (19) suggested that B7-1 can enhance
NK-mediated cytolysis which in turn facilitate priming of
tumor-specific CTL. Although the role for B7-1 in NK-mediated cytolysis
has been confirmed by several groups (34, 35), it remains
to be demonstrated whether NK cells facilitate T cell priming.
Moreover, because B7-1+ and
B7-1- tumors in the same mice have different
responses to T cells in the same environment, a systematic mechanism as
suggested by Wu et al. (19) would not explain our finding.
The fact that the function of B7-1 is almost cognate appears to argue
against the importance of IFN- up-regulation in TIL of
B7-1+ tumors. However, this possibility cannot be
ruled out because cytokine secretion is focused on the area of TCR
engagement (36), and as a result, the
B7+ tumor cells would be in an environment of
higher IFN- production.
The second issue is the implication of a role for B7 at the effector phase for tumor immunotherapy. This concept explains the slow progress in T cell based tumor immunotherapy. Alternatively, a critical role of B7 at the effector phase of T cell response provides an opportunity to increase the efficacy of cancer immunotherapy. We show here that expression of B7-1 on the tumors cells made large tumors highly susceptible to CTL therapy. However, the tumors did recur over a 10-week period, and some of the recurrent tumors lost either MHC class I or the transduced B7-1 molecule (data not shown). Thus, even if one assumes 100% efficiency of B7-1 transduction, genetic instability of tumor cells may allow tumor escape of CTL. The genetic heterogeneity can be exacerbated in large tumors, because more variants can accumulate with increasing tumor mass. Indeed, our preliminary analysis favors the notion that alteration of tumors rather than T cells is responsible for tumor recurrence, because a transfer of fresh T cells does not halt the growth of recurrent tumors. Alternatively, one may attempt to bypass such a requirement by activating B7 receptors, CD28 and CTLA4. We showed here that activating CD28 substantially enhanced the antitumor effects of P1CTL adoptive therapy, as indicated by the prolongation of mouse survival and the reduction of tumor size. Anti-CD28 mAb has been used to induce antitumor T cell response in vivo with mixed results (13, 15); our study demonstrates for the first time that the mAb enhanced local costimulation and made large tumors amenable to T cell-based immunotherapy. At face value, the effect of anti-CD28 on tumor rejection of B7- tumors and the role for B7-1 in cognate destruction of tumor cells in vivo appear at odds with each other. However, anti-CD28 can mimic the function of B7-1 at the site and time of TCR engagement by B7-1- tumor cells, whereas a given T cell is unlikely to engage B7-1+ and B7-1- tumor cells at the same time.
To demonstrate the function of CTL alone, we have chosen a model involving only one clone of T cells without the participation of other subsets of lymphocytes, including the CD4 T cells that can play a major role in maintaining the function of CD8 T cells (37). It would be of interest to further investigate whether local costimulation may offer more beneficial effects in models that involve polyclonal T cells and immunological help from CD4 T cells. Nevertheless, the requirement for B7-1 at the effector phase was initially described (14) and substantiated (19) in models where CD4 T cells are present. It is therefore important to bear in mind that this requirement is not an artifact due to a lack of CD4 T cell help.
Surprisingly, anti-CTLA4 mAb 4F10 did not increase the therapeutic efficacy of P1CTL if the mice bore only J558-Neo tumors, in sharp contrast to our recent observation that the same mAb caused rejection of the J558-Neo tumor if the mice also bore a J558-B7 tumor (data not shown). These two observations can be reconciled if B7-1 on the tumor cells and anti-CTLA4 mAbs act synergistically in promoting the effector function of antitumor immunity.
One of the most perplexing observations in cancer immunology, and certainly one of the most difficult obstacles to cancer immunotherapy, is the poor effector function of cancer-specific T cells, especially when the tumor burden is large. Our current studies indicate that effector function is reinvigorated by local costimulation, which leads to a substantial increase of the efficacy of CTL therapy for large tumors in vivo. Because cancer-specific T cells are present in cancer patients at high numbers (7, 8), increasing their effector function by local costimulation as demonstrated here, may broaden the horizon of T cell-based cancer immunotherapy.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
2 Address correspondence and reprint requests to Drs. Yang Liu and Pan Zheng, Department of Pathology and Comprehensive Cancer Center, Ohio State University Medical Center, 129 Hamilton Hall, 1645 Neil Avenue, Columbus, OH 43210. E-mail addresses: liu-3@medctr.osu.edu and zheng-1{at}medctr.osu.edu
3 Abbreviation used in this paper: TIL, tumor-infiltrating lymphocytes.
Received for publication March 9, 2001. Accepted for publication July 23, 2001.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
|
|
 |
|
  A. Bai, E. Higham, H. N. Eisen, K. D. Wittrup, and J. Chen From the Cover: Rapid tolerization of virus-activated tumor-specific CD8+ T cells in prostate tumors of TRAMP mice PNAS, September 2, 2008; 105(35): 13003 - 13008. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. F. May Jr, K. Lute, E. Kocak, S. Abdessalam, L. Yin, O. Li, Z. Guan, G. Philips, P. Zheng, and Y. Liu Immune competence of cancer-reactive T cells generated de novo in adult tumor-bearing mice Blood, January 1, 2007; 109(1): 253 - 258. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X.-F. Bai, J.-Q. Liu, P. S. Joshi, L. Wang, L. Yin, J. Labanowska, N. Heerema, P. Zheng, and Y. Liu Different Lineages of P1A-Expressing Cancer Cells Use Divergent Modes of Immune Evasion for T-Cell Adoptive Therapy Cancer Res., August 15, 2006; 66(16): 8241 - 8249. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Zheng, S. Liu, P. Wang, Y. Xu, and A. Chen Arming Tumor-Reactive T Cells with Costimulator B7-1 Enhances Therapeutic Efficacy of the T Cells. Cancer Res., July 1, 2006; 66(13): 6793 - 6799. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. B. Frey and N. Monu Effector-phase tolerance: another mechanism of how cancer escapes antitumor immune response J. Leukoc. Biol., April 1, 2006; 79(4): 652 - 662. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. P.F. Gade, W. Hassen, E. Santos, G. Gunset, A. Saudemont, M. C. Gong, R. Brentjens, X.-S. Zhong, M. Stephan, J. Stefanski, et al. Targeted Elimination of Prostate Cancer by Genetically Directed Human T Lymphocytes Cancer Res., October 1, 2005; 65(19): 9080 - 9088. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Zheng, J.-X. Gao, X. Chang, Y. Wang, Y. Liu, J. Wen, H. Zhang, J. Zhang, Y. Liu, and P. Zheng B7-CD28 Interaction Promotes Proliferation and Survival but Suppresses Differentiation of CD4-CD8- T Cells in the Thymus J. Immunol., August 15, 2004; 173(4): 2253 - 2261. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Sarma, X.-F. Bai, J.-q. Liu, K. F. May Jr., P. Zheng, and Y. Liu On the Role of Unmutated Antigens in Tumor Rejection in Mice with Unperturbed T-cell Repertoires Cancer Res., September 15, 2003; 63(18): 6051 - 6055. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. F. May Jr., L. Chen, P. Zheng, and Y. Liu Anti-4-1BB Monoclonal Antibody Enhances Rejection of Large Tumor Burden by Promoting Survival but not Clonal Expansion of Tumor-specific CD8+ T Cells Cancer Res., June 1, 2002; 62(12): 3459 - 3465. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X.-F. Bai, J. Liu, K. F. May Jr, Y. Guo, P. Zheng, and Y. Liu B7-CTLA4 interaction promotes cognate destruction of tumor cells by cytotoxic T lymphocytes in vivo Blood, April 15, 2002; 99(8): 2880 - 2889. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Liu, X.-F. Bai, J. Wen, J.-X. Gao, J. Liu, P. Lu, Y. Wang, P. Zheng, and Y. Liu B7H Costimulates Clonal Expansion of, and Cognate Destruction of Tumor Cells by, CD8+ T Lymphocytes In Vivo J. Exp. Med., November 5, 2001; 194(9): 1339 - 1348. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
