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Immunology |
1 Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research and 2 Multidisciplinary Oncology Center, University Hospital (Centre Hospitalier Universitaire Vaudois), Lausanne, Switzerland; 3 Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, Epalinges, Switzerland; 4 Department of Hematology/Oncology, University of Regensburg, Regensburg, Germany; 5 Swiss Institute for Experimental Cancer Research and 6 National Center of Competence in Research Program on Molecular Oncology, Epalinges, Switzerland; 7 Institute of Immunology and Transfusion Medicine, Ernst-Moritz-Arndt University, Greifswald, Germany
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ABSTRACT |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In this study, we present a comprehensive analysis of the function of CD8 T cells directed against the tumor differentiation antigen Melan-A/MART-1 (hereafter, Melan-A) in the following three distinct body compartments: peripheral blood, metastatic LNs, and soft tissue/visceral metastases (referred to as nonlymphoid tissue metastases). Tissue samples were collected from a series of 61 stage III/IV HLA-A2 melanoma patients. We have chosen Melan-A as a model antigen because (a) Melan-A is expressed in the majority of HLA-A2 melanoma patients (16 , 17) , (b) immunological ignorance to Melan-A is overcome in the majority of these patients (14) , and (c) high frequencies of Melan-A-specific T cells are readily detectable ex vivo (18 , 19) . We analyzed inflammatory and cytotoxic responses of Melan-A-specific CD8 T cells and compared them with those of T cells that control spreading of cytomegalovirus (CMV) infection in immune competent individuals. We provide evidence that Melan-A-specific CD8 T cells with high T-cell receptor (TCR) avidity are triggered in vivo and that they efficiently accumulate in tumor lesions (both within the lymphoid and nonlymphoid compartments) in the majority of melanoma patients. We show, however, that the tumor antigen-specific T cells in tumor lesions lack major T-cell effector functions (i.e., are functionally tolerant). Our findings highlight the importance of the microenvironment in shielding tumor cells from T-cell immune attack.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. Informed consent was obtained from all patients. The study and treatment of patients were approved by the ethical committee of the Medical Faculty, University of Lausanne, and the Ludwig Institute for Cancer Research. Thirty-eight HLA-A2 healthy subjects were blood donors at the blood transfusion center in Lausanne, Switzerland, or in Greifswald, Germany. Mononuclear cells were purified and immediately frozen as described previously (14)
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Phenotype Analysis.
CD8 T lymphocytes were positively enriched using CD8 microbeads (Miltenyi Biotec, Bergisch Gladbach, Germany), stained with multimers for 1 h at room temperature and incubated with appropriate mAbs for 20 min at 4°C. Cells were either immediately analyzed or sorted into defined populations on a FACSCalibur or a FACSVantage SE, respectively, using CellQuest software (Becton Dickinson). For intracellular staining, cells were stained with cell surface mAbs, fixed and permeabilized in PBS/1% formaldehyde/2% glucose/5 mM Na-Azid for 20 min at room temperature and incubated with mAbs in PBS/0.1% saponin for 20 min at 4°C.
IFN-
Cytospot Assay.
Measurement of intracellular IFN- production was combined with multimer labeling. Purified CD8 T cells were incubated for 4 h with T2 cells at a 1:1 ratio with either irrelevant HIV-1 Pol476–484 (ILKEPVHGV) peptide, 1 µg/ml cognate peptide, or 1 µg/ml phorbol 12-myristate 13-acetate (PMA)/0.25 µg/ml ionomycin, respectively. After 1 h, 10 µg/ml brefeldin A (Sigma, St. Louis, MO) was added. After 3 additional h, cells were stained with multimers and mAbs, fixed and permeabilized, and incubated with anti-IFN--FITC in PBS/0.1% saponin for 20 min at 4°C. Cells to be activated were stained with multimers before activation.
Quantitative PCR of TCR Excision Circles (TRECs).
Quantification of signal joint TRECs was performed by real-time quantitative PCR with the 5' nuclease (TaqMan) assay and an ABI7700 system (Applied Biosystems, Foster City, CA; Ref. 18
). The internal standard was kindly provided by Dr. D. Douek, Human Immunology Section, Vaccine Research Center, NIH. The lower limit of quantification was 101 copies of TRECs (18)
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Cytolytic Activity.
Single A2/Melan-A+ T cells were sorted ex vivo and stimulated with 1 µg/ml phytohemagglutinin-leukoagglutinin, 100 IU/ml interleukin (IL)-2, and 106/ml allogeneic-irradiated peripheral blood mononuclear cells (PBMCs). Lytic activity was measured against peptide-pulsed T2 cells (HLA-A2+, TAP–/–), and melanoma cells NA8-MEL (HLA-A2+, Melan-A–) or Me 275 (HLA-A2+, Melan-A+) in 4 h 51Cr-release assays (18)
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Lymphocyte Stimulation Assay.
Metastatic LN cells were cultured in Iscove Dulbecco‘s medium/0.55 mM Arg/0.24 mM Asn/1.5 mM Gln/8% human serum, supplemented with 30 IU/ml IL-2 and 10 ng/ml IL-7.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. Naive and antigen-experienced T cells were defined as CCR7+CD45RAhigh and non-CCR7+CD45RAhigh, respectively (21)
. In accordance with previous findings (18
, 22) , PBMCs from all healthy individuals contained detectable frequencies of Melan-A-specific T cells (mean ± SD, 0.07 ± 0.06% of CD8 T cells; Fig. 1, A and F
) that were naive (Fig. 1, A and G)
. Melan-A-specific T cells were also found in PBMCs from all melanoma patients (0.26 ± 0.45% of CD8 T cells; Fig. 1, B and F
). However, a significant fraction of these cells was antigen-experienced (45 ± 36% of Melan-A-specific T cells; Fig. 1, B and G
). The vast majority of antigen-experienced Melan-A-specific T cells displayed a CCR7–CD45RAlow phenotype (data not shown). Metastatic LNs contained on average higher frequencies of Melan-A-specific T cells (1.5 ± 2.9% of CD8 T cells; Fig. 1, C and F
) that were mostly antigen-experienced (79 ± 31% of Melan-A-specific T cells; Fig. 1, C and G
). It is noteworthy that about one-third of metastatic LNs contained frequencies of Melan-A-specific T cells that were not higher than in PBMCs of healthy individuals and were mostly naive (Fig. 1D)
, confirming the absence of Melan-A-specific T-cell immune responses in some melanoma patients (11)
. All nonlymphoid tissue metastases contained high frequencies of Melan-A-specific T cells (4.6 ± 5.8% of CD8 T cells; Fig. 1, E and F
) that were uniformly antigen-experienced (100 ± 0% of Melan-A-specific T cells; Fig. 1, E and G
). Thus, this analysis of a large series of patients confirms and extends previous observations that natural CD8 T-cell immune responses directed against Melan-A often occur in vivo (10, 11, 12
, 14
, 15
, 19
, 23
, 24)
. In particular, detectable fractions of antigen-experienced Melan-A-specific T cells accumulate in metastatic LNs and especially in nonlymphoid tissue metastases (Fig. 1H)
. Furthermore, our data clearly reveal that naive Melan-A-specific T cells are not detectable in nonlymphoid tissue metastases but are confined to peripheral blood and secondary lymphoid organs (Fig. 1I)
.
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). We first determined the relationship between the ex vivo CCR7/CD45RA phenotype and in vivo-replicative history of individual T-cell subsets by real-time PCR quantification of TRECs (18)
. Relatively high levels of TRECs were found in the naive Melan-A-specific T-cell subset, which were comparable with those found in naive peripheral CD8 T cells. In marked contrast, TREC levels were below detection in the antigen-experienced Melan-A-specific T-cell subset (Fig. 2B)
. Thus, antigen-experienced Melan-A-specific T cells in the metastatic LN had completed on average 
5 more rounds of division than their naive counterpart, in agreement with our previous findings in peripheral blood (18)
. Eight clones, referred to as N clones (derived from naive CCR7+CD45RAhigh A2/Melan-A+ cells), and six clones, referred to as AE clones (derived from antigen-experienced CCR7–CD45RAlow A2/Melan-A+ cells), were generated from the same metastatic LN. After in vitro expansion with cytokines, both N and AE clones displayed a similar and homogenous CCR7– CD45RAlow CD45RO+ CD27int CD28– CD62L– CD69int HLA-DR+ perforin+ granzyme B+ phenotype (data not shown). The relative TCR avidity of N and AE clones was compared using T2 target cells (HLA-A2+/TAP–/–) pulsed with serial dilutions of peptides corresponding to residues 26–35 (EAAGIGILTV) and 27–35 (AAGIGILTV), which mimic the naturally processed Melan-A peptides (20)
. All AE clones recognized the Melan-A26–35 peptide with relatively high avidity (IC50 ranging between 10–10 and 10–8 M; median, 10–9 M). In contrast, seven of eight N clones needed on average 103 times more peptide to achieve similar activity (IC50 ranging between 10–7 and >10–6 M, median, 10–6 M). As an exception, one of eight N clones (N11) displayed relatively high avidity for the Melan-A26–35 peptide (IC50, 10–8 M; Fig. 2C
). Similar differences in functional avidity between N and AE clones were observed when the Melan-A27–35 peptide was used. IC50 for all AE clones ranged between 10–8 and 10–7 M, whereas seven of eight N clones needed >10–6 M. Again, clone N11 selectively displayed higher functional avidity (IC50, 10–7 M; Fig. 2C
). The comparative functional avidity of N and AE clones was further analyzed by determining the stability of peptide/major histocompatibility complex class I multimer interaction with the TCR (28)
. TCR/multimer off-rates, measured in dissociation kinetic experiments, directly correlated with functional avidity, i.e., were faster for N clones as compared with AE clones (data not shown). Importantly, all of the AE clones specifically and efficiently killed the Melan-A-expressing tumor cell line Me 275, whereas the N clones (with the exception of clone N11) did not (Fig. 2D)
. Identical observations were made with Melan-A-specific T-cell clones derived from two other melanoma patients (data not shown). These observations indicate that Melan-A-specific T cells with high TCR avidity and antitumor activity were preferentially triggered and expanded in vivo.
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in peripheral blood, metastatic LNs, or nonlymphoid tissue metastases, and assessed the ability of these cells to produce IFN-, an important effector cytokine in antitumor immunity (3)
. In all blood samples tested, a high proportion (44 ± 26%; Fig. 3, A and E
) of Melan-A-specific T cells produced IFN- after short-term antigenic challenge, which was comparable with that observed after nonspecific PMA/Ionomycin stimulation (Fig. 3A)
. In sharp contrast, only 2–8% of Melan-A-specific T cells retrieved from tumor lesions (metastatic LNs and nonlymphoid tissue metastases) produced IFN- after antigenic challenge (Fig. 3, A and E)
. Importantly, the potential of these cells to produce the cytokine was intact, as shown after nonspecific PMA/Ionomycin stimulation (Fig. 3A)
. Furthermore, Melan-A-specific T cells retrieved from two metastatic LNs produced neither IL-4 nor IL-10 after antigenic or PMA/Ionomycin stimulation (data not shown). We also performed an ex vivo analysis of the intracellular content of perforin and granzyme B, two major effector molecules involved in cytotoxicity (4)
. High proportions of Melan-A-specific T cells in both PBMCs and nonlymphoid tissue metastases expressed perforin (on average 40–50%; Fig. 3, B and F
). In marked contrast, perforin was not detectable in Melan-A-specific T cells from six of nine metastatic LNs (Fig. 3, B and F)
. Similar proportions of Melan-A-specific T cells in both PBMCs and metastatic LNs expressed granzyme B in the same series of samples (Fig. 3, C and G)
. Because of limited number of cells, expression of granzyme B in nonlymphoid metastases could not be analyzed. Our results indicate that the tumor-specific T cells residing in metastatic LNs lacked the capacity to mount perforin-mediated cytotoxic responses as well as to secrete IFN- upon antigenic contact and hence were impaired with regards to both major effector pathways.
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after antigenic challenge, we wondered whether the tumor environment could also modulate their functional status. To address these issues, we analyzed the tissue distribution and effector functions of T cells that were specific for a HLA-A2-restricted nontumor antigen, such as the CMV antigen pp65495–503. CMV-specific T cells were detected in PBMCs from 27 of 38 healthy donors and 14 of 26 melanoma patients (with frequencies reaching on average 1.3% and 0.7% of CD8 T cells, respectively; Fig. 4, A and D
; Table 1
). Six metastatic LNs and five control LNs from patients who had detectable CMV-specific T cells in peripheral blood also contained detectable numbers of CMV-specific T cells, although to a lower level (on average 0.2% of CD8 T cells; Fig. 4, A and D
). In all compartments, CMV-specific T cells were mostly CCR7– (on average 92–95%; Fig. 4, A and E
) and produced IFN- after antigenic challenge or PMA/Ionomycin stimulation (on average 30–55% of CMV-specific T cells; Fig. 4, B and F
). Significant proportions of circulating CMV-specific T cells in healthy individuals and melanoma patients expressed detectable levels of perforin (on average 33–35%; Fig. 4, C and G
). In agreement with these results, fluorescence-activated cell sorter-sorted A2/CMV+ PBMCs from two healthy individuals exhibited direct cytotoxicity against T2 cells pulsed with the CMV peptide (data not shown). In marked contrast, very few CMV-specific T cells from metastatic and control LNs expressed perforin (on average 1–8%; Fig. 4, C and G
). The same phenotype analysis extended to total CD8 T cells also revealed that significant fractions expressed perforin in the peripheral blood of healthy individuals and melanoma patients (on average 25–30%, data not shown), whereas perforin expression was strongly reduced in metastatic and control LNs (on average 1–5%, data not shown). These findings indicate that cytotoxic perforin+ T cells do not reside in LNs and thus support the notion that the perforin deficit observed in tumor-specific T cells from metastatic LNs is a consequence of the LN environment itself and not the tumor. In contrast, the capacity to produce IFN- in response to antigen was selectively preserved by LN-derived virus-specific T cells. Impaired IFN- production by LN-derived tumor-specific T cells is likely attributable to the tumor and not to the LN environment.
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after antigenic challenge (Fig. 5A)
, and expressed intracellular perforin (Fig. 5B)
already after 2 days of culture. Production of IFN- by Melan-A-specific T cells was also observed in metastatic LN cultures from two other patients (data not shown). Because proliferation of Melan-A-specific T cells was only observed after 4–6 days of culture (as assessed by 5,6-carboxylfluorescein diacetate succinimidyl ester labeling; Fig. 5C
), both effector functions were acquired before cell division. The acquisition of potent effector functions by in vitro-cultured tumor-specific T cells is in line with previous observations (11
, 14)
. Altogether, these findings underscore the necessity of analyzing T cells directly ex vivo for a correct assessment of their effector functions.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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As a result of direct thymic output, naive (CCR7+CD45RAhigh) Melan-A-specific T cells are detectable by specific multimer staining in peripheral blood of HLA-A2 healthy individuals and melanoma patients (18) . As shown here, the presence of naive Melan-A-specific T cells in LNs of melanoma patients suggests a continuous trafficking from the blood to secondary lymphoid organs, in line with the pivotal role of CCR7 in lymphocyte migration to LNs (32) . This is further supported by our finding that naive Melan-A-specific T cells are not detected in nonlymphoid tissue metastases. Melan-A-specific T cells remain naive in healthy individuals despite the presence of antigen in melanocytes, a phenomenon akin to immunological ignorance. In contrast, a significant fraction of these cells becomes activated in some melanoma patients (10, 11, 12 , 14 , 19 , 23 , 24) . Here, we found that immunological ignorance to Melan-A was overcome at least in 26 of 40 (65%) patients. As indicated by our analysis of TREC levels, the high frequency of antigen-experienced Melan-A-specific T cells is the result of extensive in vivo proliferation. Importantly, the naturally occurring immune responses observed in this study with a large series of melanoma patients were able to generate tumor-specific T cells that were "fit" in peripheral blood (i.e., antigen-experienced circulating Melan-A-specific T cells displayed robust cytotoxic and inflammatory activities). Hence, we extend previous observations that circulating tumor-specific T cells exhibit the two major effector functions involved in tumor protection and suggest that anergy, as reported previously for one melanoma patient (12) , is not a common feature of T cells directed against tumor-differentiation antigens.
The coexistence of both naive and antigen-experienced Melan-A-specific T cells within the same LN allowed us to investigate whether T cells with high TCR avidity were selected during natural antitumor immune responses. Indeed, whereas previous work showed that the naive Melan-A-specific T-cell pool is composed of cells that exhibit a broad range of functional avidities (25) , we found here that the antigen-experienced T-cell repertoire consisted only of cells with high TCR avidity (33) . Limiting amounts of antigenic peptides available in vivo may account for this selection process. In addition, because high avidity T cells represent only a minority of the naive Melan-A-specific T-cell pool, our data may explain why the size of the latter remained stable (on average 0.07% of CD8 T cells) in LNs, irrespective of the presence or absence of antigen-experienced T cells. Alternatively, independent homeostatic regulation of naive and antigen-experienced T-cell populations (34) and repopulation of the naive T-cell pool with recent thymic emigrants (35) may also explain the stable size of the naive Melan-A-specific T-cell pool observed in LNs from patients with documented natural responses.
A tolerant state of potentially tumor-reactive T cells has been documented both in mouse models and humans (6, 7, 8)
. In this study, we report on the direct functional characterization of single tumor-specific T cells, by measuring their cytotoxic and inflammatory effector activities, and we illustrate that these cells are selectively tolerant within tumor lesions. Melan-A-specific T cells residing in metastatic LNs were functionally tolerant with regard to both effector pathways. On one hand, the tumor-specific T cells did not display perforin-mediated cytotoxic activities. Virus-specific T cells present in metastatic and control LNs also contained undetectable or low levels of perforin. This observation was further confirmed by the analysis of total CD8 LN-derived T cells, potentially including tumor-specific T cells with specificity for antigens other than Melan-A. Absence of perforin in LN-derived T cells was associated with CD27 expression (data not shown), a feature of circulating virus-specific T cells with incomplete functional maturation (36)
. Granzyme B was expressed by a significant proportion of tumor-specific T cells. However, because of the essential role of perforin for appropriate delivery of granzyme B, these cells were presumably unable to induce target-cell apoptosis (4)
. These findings may be explained by the migratory properties of fully activated effector CD8 T cells, which leave the LN and home to peripheral tissues. Accordingly, Melan-A-specific T cells with cytotoxic effector activities were found in the peripheral blood and nonlymphoid tissues of some melanoma patients. It is worth noting that Melan-A+ metastatic tumor cells, in some instances present at elevated numbers in the LNs, were not able to revert the homing properties of the cytotoxic T cells. On the other hand, the tumor-specific T cells present in metastatic LNs of the majority of melanoma patients also lacked the capacity to secrete IFN- after antigenic challenge. Because this function was preserved for virus-specific T cells in both metastatic and control LNs, we propose that the tumor (and not the LN) environment is responsible for the IFN- deficit exhibited by the tumor-specific T cells. Interestingly, lack of IFN- production by enterocyte antigen-specific T cells that have homed to the intestine was also described as a mechanism for maintenance of tolerance to self in a transgenic mouse model (37
, 38)
. Altogether, our findings suggest that both the homing properties of antigen-primed T cells as well as the tumor environment affect the two major CD8 T-cell effector functions. Overall, the absence of functionally active tumor-specific T cells in metastatic LNs likely explains the frequent failure of the immune system to eliminate LN tumor metastases. In contrast to a previous report describing anergic tyrosinase-specific T cells in one patient (12)
, the functional tolerance identified for tumor-specific T cells in this study were rapidly reversible in vitro. Interestingly, a recent study showed that the functionally tolerant state of self/tumor antigen-specific T cells could be reversed in mice after therapy with T cells, altered peptide, and IL-2 (39)
. Coadministration of the cytokine was required to induce the destruction of poorly immunogenic established melanoma tumors.
The effector functions observed for Melan-A-specific T cells in nonlymphoid tissue metastases were also considerably reduced. However, in contrast to those residing in metastatic LNs, these cells expressed detectable levels of perforin and thus were apparently able to mediate cytotoxic activity. This finding supports the notion mentioned above that paucity of perforin expression is a feature of T cells residing in lymphoid tissues. Nevertheless, Melan-A-specific T cells failed to produce IFN- in both metastatic LNs and nonlymphoid tissue metastases. Thus, IFN- secretion was turned off when the tumor-specific T cells were in the presence of melanoma cells in vivo. Although several mechanisms of tumor-induced immune defects have been proposed, including alterations in signal transduction (40
, 41)
, functional unresponsiveness (42)
, and immunosuppressive environment (8
, 43) , the robust production of IFN- by tumor-specific cells observed after stimulation with PMA and ionomycin suggests disruption of signaling events proximal to the TCR. Given the key role of IFN- in the newly rekindled concept of cancer immunosurveillance (3)
, it is conceivable that the inability of tumor antigen-specific T cells to produce this cytokine critically reduces their protective potential. Understanding the mechanisms involved in the generation and/or maintenance of the functional tolerance of tumor-specific T cells in tumor lesions described in this study may provide the framework for improving the efficiency of cancer immunotherapy.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Note: M. J. Pittet is currently at the Center for Molecular Imaging Research, Massachusetts General Hospital, Harvard Medical School, Building 149, 13th Street, Room 5029, Charlestown, MA 02129. A. Zippelius is currently at the Department of Oncology, University Hospital Zurich, 8091 Zurich, Switzerland.
Requests for reprints: Mikaël J. Pittet, Center for Molecular Imaging Research, Massachusetts General Hospital, Harvard Medical School, Building 149, 13th Street, Room 5029, Charlestown, MA 02129. Phone: 1-617-726-5788; Fax: 1-617-726-5708; E-mail: mpittet@hms.harvard.edu or Pedro Romero, Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, Hôpital Orthopédique, Niveau 5, Aile est, Avenue Pierre Decker 4, 1005 Lausanne, Switzerland. E-mail: pedro.romero{at}isrec.unil.ch
Received 9/30/03. Revised 1/28/04. Accepted 2/10/04.
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L. Derre, M. Ferber, C. Touvrey, E. Devevre, V. Zoete, A. Leimgruber, P. Romero, O. Michielin, F. Levy, and D. E. Speiser A Novel Population of Human Melanoma-Specific CD8 T Cells Recognizes Melan-AMART-1 Immunodominant Nonapeptide but Not the Corresponding Decapeptide J. Immunol., December 1, 2007; 179(11): 7635 - 7645. [Abstract] [Full Text] [PDF]
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A. Shanker, G. Verdeil, M. Buferne, E.-M. Inderberg-Suso, D. Puthier, F. Joly, C. Nguyen, L. Leserman, N. Auphan-Anezin, and A.-M. Schmitt-Verhulst CD8 T Cell Help for Innate Antitumor Immunity J. Immunol., November 15, 2007; 179(10): 6651 - 6662. [Abstract] [Full Text] [PDF]
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T. F. Gajewski Failure at the Effector Phase: Immune Barriers at the Level of the Melanoma Tumor Microenvironment Clin. Cancer Res., September 15, 2007; 13(18): 5256 - 5261. [Abstract] [Full Text] [PDF]
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M. J. Pittet, J. Grimm, C. R. Berger, T. Tamura, G. Wojtkiewicz, M. Nahrendorf, P. Romero, F. K. Swirski, and R. Weissleder In vivo imaging of T cell delivery to tumors after adoptive transfer therapy PNAS, July 24, 2007; 104(30): 12457 - 12461. [Abstract] [Full Text] [PDF]
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J. M. Curtsinger, M. Y. Gerner, D. C. Lins, and M. F. Mescher Signal 3 Availability Limits the CD8 T Cell Response to a Solid Tumor J. Immunol., June 1, 2007; 178(11): 6752 - 6760. [Abstract] [Full Text] [PDF]
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N. Suciu-Foca, N. Feirt, Q.-Y. Zhang, G. Vlad, Z. Liu, H. Lin, C.-C. Chang, E. K. Ho, A. I. Colovai, H. Kaufman, et al. Soluble Ig-Like Transcript 3 Inhibits Tumor Allograft Rejection in Humanized SCID Mice and T Cell Responses in Cancer Patients J. Immunol., June 1, 2007; 178(11): 7432 - 7441. [Abstract] [Full Text] [PDF]
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K. Fischer, P. Hoffmann, S. Voelkl, N. Meidenbauer, J. Ammer, M. Edinger, E. Gottfried, S. Schwarz, G. Rothe, S. Hoves, et al. Inhibitory effect of tumor cell-derived lactic acid on human T cells Blood, May 1, 2007; 109(9): 3812 - 3819. [Abstract] [Full Text] [PDF]
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C. Barbey, P. Baumgaertner, E. Devevre, V. Rubio-Godoy, L. Derre, G. Bricard, P. Guillaume, I. F. Luescher, D. Lienard, J.-C. Cerottini, et al. IL-12 Controls Cytotoxicity of a Novel Subset of Self-Antigen-Specific Human CD28+ Cytolytic T Cells J. Immunol., March 15, 2007; 178(6): 3566 - 3574. [Abstract] [Full Text] [PDF]
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L. Strauss, T. L. Whiteside, A. Knights, C. Bergmann, A. Knuth, and A. Zippelius Selective Survival of Naturally Occurring Human CD4+CD25+Foxp3+ Regulatory T Cells Cultured with Rapamycin J. Immunol., January 1, 2007; 178(1): 320 - 329. [Abstract] [Full Text] [PDF]
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A. Ghochikyan, M. Mkrtichyan, D. Loukinov, G. Mamikonyan, S. D. Pack, N. Movsesyan, T. E. Ichim, D. H. Cribbs, V. V. Lobanenkov, and M. G. Agadjanyan Elicitation of T Cell Responses to Histologically Unrelated Tumors by Immunization with the Novel Cancer-Testis Antigen, Brother of the Regulator of Imprinted Sites J. Immunol., January 1, 2007; 178(1): 566 - 573. [Abstract] [Full Text] [PDF]
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J. Tabiasco, E. Devevre, N. Rufer, B. Salaun, J.-C. Cerottini, D. Speiser, and P. Romero Human Effector CD8+ T Lymphocytes Express TLR3 as a Functional Coreceptor J. Immunol., December 15, 2006; 177(12): 8708 - 8713. [Abstract] [Full Text] [PDF]
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V. Cesson, K. Stirnemann, B. Robert, I. Luescher, T. Filleron, G. Corradin, J.-P. Mach, and A. Donda Active Antiviral T-Lymphocyte Response Can Be Redirected against Tumor Cells by Antitumor Antibody x MHC/Viral Peptide Conjugates Clin. Cancer Res., December 15, 2006; 12(24): 7422 - 7430. [Abstract] [Full Text] [PDF]
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S. M. Walton, M. Gerlinger, O. de la Rosa, N. Nuber, A. Knights, A. Gati, M. Laumer, L. Strauss, C. Exner, N. Schafer, et al. Spontaneous CD8 T Cell Responses against the Melanocyte Differentiation Antigen RAB38/NY-MEL-1 in Melanoma Patients J. Immunol., December 1, 2006; 177(11): 8212 - 8218. [Abstract] [Full Text] [PDF]
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G. Bioley, C. Jandus, S. Tuyaerts, D. Rimoldi, W. W. Kwok, D. E. Speiser, J.-M. Tiercy, K. Thielemans, J.-C. Cerottini, and P. Romero Melan-A/MART-1-Specific CD4 T Cells in Melanoma Patients: Identification of New Epitopes and Ex Vivo Visualization of Specific T Cells by MHC Class II Tetramers J. Immunol., November 15, 2006; 177(10): 6769 - 6779. [Abstract] [Full Text] [PDF]
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K. M. Hargadon, C. C. Brinkman, S. L. Sheasley-O'Neill, L. A. Nichols, T. N. J. Bullock, and V. H. Engelhard Incomplete Differentiation of Antigen-Specific CD8 T Cells in Tumor-Draining Lymph Nodes J. Immunol., November 1, 2006; 177(9): 6081 - 6090. [Abstract] [Full Text] [PDF]
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I. E. Brown, C. Blank, J. Kline, A. K. Kacha, and T. F. Gajewski Homeostatic Proliferation as an Isolated Variable Reverses CD8+ T Cell Anergy and Promotes Tumor Rejection J. Immunol., October 1, 2006; 177(7): 4521 - 4529. [Abstract] [Full Text] [PDF]
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V. Appay, C. Jandus, V. Voelter, S. Reynard, S. E. Coupland, D. Rimoldi, D. Lienard, P. Guillaume, A. M. Krieg, J.-C. Cerottini, et al. New Generation Vaccine Induces Effective Melanoma-Specific CD8+ T Cells in the Circulation but Not in the Tumor Site J. Immunol., August 1, 2006; 177(3): 1670 - 1678. [Abstract] [Full Text] [PDF]
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D. E. Speiser, P. Baumgaertner, C. Barbey, V. Rubio-Godoy, A. Moulin, P. Corthesy, E. Devevre, P.-Y. Dietrich, D. Rimoldi, D. Lienard, et al. A Novel Approach to Characterize Clonality and Differentiation of Human Melanoma-Specific T Cell Responses: Spontaneous Priming and Efficient Boosting by Vaccination J. Immunol., July 15, 2006; 177(2): 1338 - 1348. [Abstract] [Full Text] [PDF]
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W. W. Overwijk, K. E. de Visser, F. H. Tirion, L. A. de Jong, T. W. H. Pols, Y. U. van der Velden, J. G. van den Boorn, A. M. Keller, W. A. Buurman, M. R. Theoret, et al. Immunological and Antitumor Effects of IL-23 as a Cancer Vaccine Adjuvant J. Immunol., May 1, 2006; 176(9): 5213 - 5222. [Abstract] [Full Text] [PDF]
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R. J.C.L.M. Vuylsteke, B. G. Molenkamp, P. A.M. van Leeuwen, S. Meijer, P. G.J.T.B. Wijnands, J. B.A.G. Haanen, R. J. Scheper, and T. D. de Gruijl Tumor-Specific CD8+ T Cell Reactivity in the Sentinel Lymph Node of GM-CSF-Treated Stage I Melanoma Patients is Associated with High Myeloid Dendritic Cell Content. Clin. Cancer Res., May 1, 2006; 12(9): 2826 - 2833. [Abstract] [Full Text] [PDF]
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 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]
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T. F. Gajewski Identifying and overcoming immune resistance mechanisms in the melanoma tumor microenvironment. Clin. Cancer Res., April 1, 2006; 12(7): 2326s - 2330s. [Abstract] [Full Text] [PDF]
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G. Lizee, L. G. Radvanyi, W. W. Overwijk, and P. Hwu Immunosuppression in melanoma immunotherapy: potential opportunities for intervention. Clin. Cancer Res., April 1, 2006; 12(7): 2359s - 2365s. [Abstract] [Full Text] [PDF]
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M. J. Pittet, A. Gati, F.-A. Le Gal, G. Bioley, P. Guillaume, M. de Smedt, J. Plum, D. E. Speiser, J.-C. Cerottini, P.-Y. Dietrich, et al. Ex Vivo Characterization of Allo-MHC-Restricted T Cells Specific for a Single MHC-Peptide Complex J. Immunol., February 15, 2006; 176(4): 2330 - 2336. [Abstract] [Full Text] [PDF]
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L. Duval, H. Schmidt, K. Kaltoft, K. Fode, J. J. Jensen, S. M. Sorensen, M. I. Nishimura, and H. von der Maase Adoptive Transfer of Allogeneic Cytotoxic T Lymphocytes Equipped with a HLA-A2 Restricted MART-1 T-Cell Receptor: A Phase I Trial in Metastatic Melanoma Clin. Cancer Res., February 15, 2006; 12(4): 1229 - 1236. [Abstract] [Full Text] [PDF]
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N. Hirano, M. O. Butler, Z. Xia, S. Ansen, M. S. von Bergwelt-Baildon, D. Neuberg, G. J. Freeman, and L. M. Nadler Engagement of CD83 ligand induces prolonged expansion of CD8+ T cells and preferential enrichment for antigen specificity Blood, February 15, 2006; 107(4): 1528 - 1536. [Abstract] [Full Text] [PDF]
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S. Mocellin, F. M. Marincola, and H. A. Young Interleukin-10 and the immune response against cancer: a counterpoint J. Leukoc. Biol., November 1, 2005; 78(5): 1043 - 1051. [Abstract] [Full Text] [PDF]
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S. Kusmartsev, S. Nagaraj, and D. I. Gabrilovich Tumor-Associated CD8+ T Cell Tolerance Induced by Bone Marrow-Derived Immature Myeloid Cells J. Immunol., October 1, 2005; 175(7): 4583 - 4592. [Abstract] [Full Text] [PDF]
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Y. Li, M. Bleakley, and C. Yee IL-21 Influences the Frequency, Phenotype, and Affinity of the Antigen-Specific CD8 T Cell Response J. Immunol., August 15, 2005; 175(4): 2261 - 2269. [Abstract] [Full Text] [PDF]
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K. Liu, S. A. Caldwell, and S. I. Abrams Immune Selection and Emergence of Aggressive Tumor Variants as Negative Consequences of Fas-Mediated Cytotoxicity and Altered IFN-{gamma}-Regulated Gene Expression Cancer Res., May 15, 2005; 65(10): 4376 - 4388. [Abstract] [Full Text] [PDF]
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 V. Bronte, T. Kasic, G. Gri, K. Gallana, G. Borsellino, I. Marigo, L. Battistini, M. Iafrate, T. Prayer-Galetti, F. Pagano, et al. Boosting antitumor responses of T lymphocytes infiltrating human prostate cancers J. Exp. Med., April 18, 2005; 201(8): 1257 - 1268. [Abstract] [Full Text] [PDF]
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C. Germeau, W. Ma, F. Schiavetti, C. Lurquin, E. Henry, N. Vigneron, F. Brasseur, B. Lethe, E. De Plaen, T. Velu, et al. High frequency of antitumor T cells in the blood of melanoma patients before and after vaccination with tumor antigens J. Exp. Med., January 18, 2005; 201(2): 241 - 248. [Abstract] [Full Text] [PDF]
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M.-L. Chen, M. J. Pittet, L. Gorelik, R. A. Flavell, R. Weissleder, H. von Boehmer, and K. Khazaie Regulatory T cells suppress tumor-specific CD8 T cell cytotoxicity through TGF-{beta} signals in vivo PNAS, January 11, 2005; 102(2): 419 - 424. [Abstract] [Full Text] [PDF]
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N. Meidenbauer, A. Zippelius, M. J. Pittet, M. Laumer, S. Vogl, J. Heymann, M. Rehli, B. Seliger, S. Schwarz, F.-A. L. Gal, et al. High Frequency of Functionally Active Melan-A-Specific T Cells in a Patient with Progressive Immunoproteasome-Deficient Melanoma Cancer Res., September 1, 2004; 64(17): 6319 - 6326. [Abstract] [Full Text] [PDF]
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