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  • BONE-MARROW  (23)
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  • 1
    Keywords: CANCER ; CELLS ; EXPRESSION ; Germany ; IN-VIVO ; ADHESION MOLECULES ; MICE ; COMPLEX ; COMPLEXES ; tumour ; ANTIGEN ; CONTRAST ; DENDRITIC CELLS ; T-CELL ; T-CELLS ; FREQUENCY ; MOLECULE ; bone marrow ; BONE-MARROW ; virus ; LINE ; ADHESION ; NAIVE ; ADHESION MOLECULE ; EFFECTOR ; adoptive immunotherapy ; FEATURES ; RE ; CLASS-II ; PROTECTIVE IMMUNITY ; memory T cells ; PERSISTENCE ; CD8(+) T-cell memory ; GAMMA-IRRADIATION ; LYMPHOCYTES-T ; tumour dormancy
    Abstract: LacZ (Gal)-reactive immune cells were transferred into athymic nu/nu mice inoculated with Gal-expressing syngeneic tumour cells (ESbL-Gal) in order to study tumour-protective T-cell memory. This transfer prevented tumour outgrowth in recipients and resulted in the persistence of a high frequency of Gal-specific CD8(+) T cells in the bone marrow and spleen. In contrast, such Ag-specific memory CD8(+) T cells were not detectable by peptide-major histocompatibility complex (MHC) multimer staining in animals that had not previously received an antigenic challenge. Even though CD44(hi) memory T cells from the bone marrow showed a significantly higher turnover rate, as judged by bromodeoxyuridine (BrdU) incorporation, than respective cells from spleen or lymph nodes, as well as in comparison to CD44(lo) naive T cells, these findings suggest that tumour-associated antigen (TAA) from residual dormant tumour cells are implicated in maintaining high frequencies of long-term surviving Gal-specific memory CD8(+) T cells. Memory T cells could be recruited to the peritoneal cavity by tumour vaccination of immunoprotected nu/nu mice and exhibited ex vivo antitumour reactivity. Long-term immune memory and tumour protection could be maintained over four successive transfers between tumour-inoculated recipients, which involved periodic antigenic restimulation in vivo prior to reisolating the cells for adoptive transfer. Using a cell line (ESbL-Gal-BM) that was established from dormant tumour cells isolated from the bone marrow of immunoprotected animals, it could be demonstrated that the tumour cells had up-regulated the expression of MHC class I molecules and down-regulated the expression of several adhesion molecules during the in vivo passage. Our results suggest that the bone marrow microenvironment has special features that are of importance for the maintenance of tumour dormancy and immunological T-cell memory, and that a low level of persisting antigen favours the maintenance of Ag-specific memory T cells over irrelevant memory T cells
    Type of Publication: Journal article published
    PubMed ID: 15946250
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  • 2
    Keywords: CANCER ; CELLS ; SURVIVAL ; tumor ; TUMOR-CELLS ; Germany ; MODEL ; MODELS ; THERAPY ; PATIENT ; ACTIVATION ; RESPONSES ; INFECTION ; ANTIGEN ; DENDRITIC CELLS ; T-CELL ; T-CELLS ; bone marrow ; BONE-MARROW ; IMMUNE-RESPONSES ; virus ; TRIAL ; CLINICAL-TRIALS ; LONG-TERM SURVIVAL ; Jun ; VACCINE ; IMMUNE-RESPONSE ; IMMUNOTHERAPY ; INTERFERON-ALPHA ; CANCER PATIENTS ; tumor vaccine ; APOPTOSIS-INDUCING LIGAND ; PHASE-II ; STANDARD ; RE ; PATIENT SURVIVAL ; ACTIVE-SPECIFIC IMMUNOTHERAPY ; NEWCASTLE-DISEASE-VIRUS ; DELAYED-TYPE HYPERSENSITIVITY ; dendritic cell ; PHASE ; Newcastle disease virus ; tumor-antigen ; memory T cells ; phase II ; COLORECTAL-CANCER PATIENTS ; METASTATIC SPREAD ; POSTOPERATIVE IMMUNOTHERAPY
    Abstract: For active specific immunotherapy of cancer patients, we designed the autologous virus-modified tumor cell vaccine ATV-NDV. The rationale of this vaccine is to link multiple tumor-associated antigens (TAAs) from individual patient-derived tumor cells with multiple danger signals (DS) derived from virus infection (dsRNA, HN, IFN-alpha). This allows activation of multiple innate immune responses (monocytes, dendritic cells, and NK cells) as well as adaptive immune responses (CD4 and CD8 memory T cells). Preexisting antitumor memory T cells from cancer patients could be activated by antitumor vaccination with ATV-NDV as seen by augmentation of antitumor memory delayed-type hypersensitivity (DTH) responses. In a variety of phase II vaccination studies, an optimal formulation of this vaccine could improve long-term survival beyond what is seen in conventional standard therapies. A new concept is presented which proposes that a certain threshold of antitumor immune memory plays an important role (1) in the control of residual tumor cells which remain after most therapies and (2) for long-term survival of treated cancer patients. This immune memory is T-cell based and most likely maintained by persisting TAAs from residual dormant tumor cells. Such immune memory was prominent in the bone marrow in animal tumor models as well as in cancer patients. Immunization with a tumor vaccine in which individual TAAs are combined with DS from virus infection appears to have a positive effect on antitumor immune memory and on patient survival
    Type of Publication: Journal article published
    PubMed ID: 15838708
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  • 3
    Keywords: CANCER ; CELLS ; tumor ; Germany ; IN-VIVO ; MODEL ; DISEASE ; MICE ; RESPONSES ; DONOR ; GRAFT ; ANTIGEN ; T-CELL ; T-CELLS ; FREQUENCY ; bone marrow ; BONE-MARROW ; IMMUNE-RESPONSES ; MEMORY ; NOD/Scid mice ; NUMBER ; leukemia ; LYMPHOCYTES ; graft-versus-leukemia ; IMMUNE-RESPONSE ; NAIVE ; HOST-DISEASE ; METASTATIC TUMOR ; SINGLE ; RE ; LIFE ; PROTECTIVE IMMUNITY ; memory T cells ; REMISSION ; ADOPTIVE TRANSFER ; MINOR HISTOCOMPATIBILITY ANTIGENS ; bone marrow cells ; immune memory T cells
    Abstract: The bone marrow has been shown to represent a unique microenvironment where T cell immune responses against tumor associated antigens can be initiated and tumor-immune memory T cells are enriched. In the present Study the graft versus leukemia (GvL) reactivity of bone marrow derived tumor-immune memory T cells was analyzed in an allogeneic minor histocompatibility different murine GvL tumor model with late stage disease. A single adoptive cell transfer of B10.D2 donor immune bone marrow cells (iBM) into sub-lethally irradiated late stage ESb-MP tumor-bearing DBA/2 mice led to a complete tumor remission and to significant life prolongation. Even though the frequency of bone marrow resident T cells is only around 2%, the GvL reactivity of iBM was superior to immune cells from the spleen (iSPL) or to those from the peritoneal cavity (iPEC) of the same immunized donors. iPEC exerted mostly unwanted graft versus host (GvH) reactivity, while iSPL exerted GvL and GvH reactivity. Bone marrow cells from naive donor mice or T cell depleted iBM cells were completely devoid of GvL reactivity. The low number of tumor-immune memory T cells thus conferred the GvL reactivity of iBM cells
    Type of Publication: Journal article published
    PubMed ID: 16142333
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  • 4
    Keywords: CANCER ; CELLS ; tumor ; carcinoma ; Germany ; GENERATION ; PATIENT ; IFN-GAMMA ; DONOR ; ANTIGEN ; ANTIGENS ; T cells ; T-CELLS ; FREQUENCY ; FREQUENCIES ; bone marrow ; BONE-MARROW ; BREAST ; breast cancer ; BREAST-CANCER ; TRANSGENIC MICE ; IDENTIFICATION ; DESIGN ; COLORECTAL-CANCER ; LYMPHOCYTES ; PEPTIDES ; VACCINE ; CANCER-PATIENTS ; INDIVIDUALS ; T-LYMPHOCYTES ; MELANOMA PATIENTS ; CANCER PATIENTS ; T lymphocytes ; TUMOR-ASSOCIATED ANTIGENS ; CLASS-I MOLECULES ; RE ; BONE ; RELEVANCE ; healthy individuals ; SHORT-TERM ; LYMPHOCYTE LINES
    Abstract: We analyzed the T-cell repertoires from the bone marrow of 39 primary operated breast cancer patients and 11 healthy female donors for the presence and frequencies of spontaneously induced effector/memory T lymphocytes with peptide-HLA-A2-restricted reactivity against 10 breast tumor-associated antigens (TAA) and 3 normal breast tissue-associated antigens by short-term IFN-gamma enzyme-linked inummospot (ELISpot) analysis. Sixty-seven percent of the patients recognized TAAs with a mean frequency of 144 TAA reactive cells per 106 T cells. These patients recognized simultaneously an average of 47% of the tested TAAs. The T-cell repertoire was highly polyvalent and exhibited pronounced interindividual differences in the pattern of TAAs recognized by each patient., Strong differences of reactivity were noticed between TAAs, ranging from 100% recognition of prostate-specific antigen(p141-149) to only 25% recognition of MUC1(p12-20) or Her-2/neu(p369-377). In comparison with TAAs reactivity to normal breast tissue-associated antigens was lower with respect to the proportions of responding patients (30%) and recognized antigens (27%), with a mean frequency of only 85/10(6) T cells. Healthy individuals also contained TAA-reactive T cells but this repertoire was more restricted and the frequencies were in the same range as T cells reacting to normal breast tissue-associated antigens. Our data show a highly individual T-cell repertoire for recognition of TAAs in breast cancer patients. This has potential relevance for T-cell immune diagnostics, for tumor vaccine design, and for predicting immune responsiveness
    Type of Publication: Journal article published
    PubMed ID: 16912206
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  • 5
    Keywords: CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; tumor ; TUMOR-CELLS ; BLOOD ; carcinoma ; Germany ; IN-VIVO ; THERAPY ; DISEASE ; PATIENT ; IFN-GAMMA ; ANTIGEN ; T cells ; T-CELLS ; bone marrow ; BONE-MARROW ; BREAST-CANCER ; CANCER-CELLS ; antigen presentation ; CANCER-PATIENTS ; IMMUNOTHERAPY ; PERIPHERAL-BLOOD ; pancreatic cancer ; pancreatic carcinoma ; INTERFERON-GAMMA ; CYTOKINE ; RE ; PANCREATIC-CANCER ; pancreatic ; TUMOR-CELL ; T helper cell ; HLA-A ; BONE ; peripheral blood ; ANTIGEN EXPRESSION ; B-ANTIGEN ; tumor-specific T cells
    Abstract: Pancreatic carcinoma is a very aggressive disease and little is known about its immunobiology. We here describe the presence in pancreatic cancer patients of spontaneously induced functional CD4 and CD8 memory/effector T cells reactive to autologous tumor cells or to the pancreatic cancer associated antigen, MUC-1. Such specific cells were present in the bone marrow or peripheral blood of most of the 23 tested patients. Low dose stimulation of primary cultures of pancreatic cancer cells with 500 IU/ml IFN-gamma for 72 h enhanced HLA-I expression and induced the de novo expression of HLA-II molecules. This led to a much better immune recognition by autologous HLA-I restricted and purified CD8 T cells and allowed tumor cell recognition by HLA-II restricted purified CD4 T-helper cells. Thus, interferon-gamma appears to be a useful adjuvant cytokine to enhance the immunogenicity of a patients' tumor cells and their recognition by tumor reactive immune cells
    Type of Publication: Journal article published
    PubMed ID: 16685444
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  • 6
    Keywords: CANCER ; CELLS ; EXPRESSION ; IN-VITRO ; tumor ; TUMOR-CELLS ; carcinoma ; CELL ; Germany ; human ; THERAPY ; VITRO ; DISEASE ; EXPOSURE ; SITE ; GENE ; PATIENT ; ACTIVATION ; IFN-GAMMA ; MARKER ; LYMPH-NODES ; T cell ; T cells ; T-CELL ; T-CELLS ; BONE-MARROW ; MEMORY ; STIMULATION ; virus ; ASSAY ; PARAMETERS ; HEAD ; VACCINE ; REPLICATION ; squamous cell carcinoma ; ELISPOT ; IMMUNOTHERAPY ; vaccination ; side effects ; IL-2 ; FUSION PROTEIN ; INTERLEUKIN-2 ; INCREASED EXPRESSION ; CELL CARCINOMA ; FEATURES ; ONCOLOGY ; RECOMBINANT ; NODES ; RE ; HNSCC ; NEWCASTLE-DISEASE-VIRUS ; Newcastle disease virus ; lymph nodes ; ANTITUMOR VACCINATION ; SQUAMOUS-CELL ; systemic ; DEGRANULATION ; cancer vaccination ; CYTOTOXIC ACTIVITY ; tumor therapy ; anti-tumor activity ; anti-tumor ; interleukin 2
    Abstract: A new recombinant (rec) Newcastle disease virus (NDV) with incorporated human interleukin 2 (IL-2) as foreign therapeutic gene [rec(IL-2)] will be described. The foreign gene in rec(IL-2) did not affect the main features of NDV replication nor its tumor selectivity. Biologically active IL-2 was produced in high amounts by tumor cells infected with rec(IL-2). Tumor vaccine cells infected by rec(IL-2) stimulated human T cells to exert anti-tumor activity in vitro in a tumor neutralization assay. These effects were significantly increased when compared to vaccine infected by rec(-) virus without IL-2 gene. After incubation with rec(IL-2) infected tumor cells, T cells showed increased expression of the activation marker CD69 and produced increased amounts of IFN gamma when compared to T cells co-incubated with rec(-) infected tumor cells. CD8 T cells incubated with rec(IL-2) infected tumor cells showed upregulation of perform, cell surface exposure of the degranulation marker CD107a and increased anti-tumor cytotoxic activity. Purified T cells from lymph nodes of head and neck squamous cell carcinoma (HNSCC) patients could be stimulated to secrete IFN gamma in an ELISPOT assay upon 40 h of stimulation with rec(IL-2) infected autologous tumor cells [ATV-rec(IL-2)] but not upon stimulation with rec(IL-2) infected allogeneic U937 tumor cells. This suggests direct activation of patient derived tumor antigen-specific memory T cells by ATV-rec(IL-2). In conclusion, the already inherent immunostimulatory properties of NDV could be further augmented by the introduction of the therapeutic gene IL-2. Active specific immunization of patients with ATV-rec(IL-2) should provide the microenvironment at the vaccination site with IL-2 and avoid side effects as seen after systemic IL-2 application
    Type of Publication: Journal article published
    PubMed ID: 18813797
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  • 7
    Keywords: RECEPTOR ; CANCER ; CELLS ; EXPRESSION ; GROWTH ; IN-VITRO ; proliferation ; tumor ; human ; IN-VIVO ; MODEL ; THERAPY ; TISSUE ; TUMORS ; MICE ; TUMOR-NECROSIS-FACTOR ; RECEPTOR EXPRESSION ; INDEX ; primary ; BONE-MARROW ; BREAST ; breast cancer ; BREAST-CANCER ; NOD/Scid mice ; PROGRESSION ; PATTERNS ; TUMOR PROGRESSION ; breast cancer xenotransplantation ; CELL THERAPY ; cellular adoptive transfer ; DUAL ROLE ; graft-vs.- host disease ; HUMAN-TUMORS ; IMMUNODEFICIENT MICE ; IMPLANTATION ; metastases ; NECROSIS-FACTOR-ALPHA ; NUDE-MICE ; SCID MOUSE ; tumor-infiltrating lymphocytes
    Abstract: We describe a new human tumor xenotransplant animal model that is highly efficient for engraftment, does not need host conditioning and is suitable for in vivo studies of human tumors. Pieces of 61 freshly operated primary breast tumors were implanted into 172 irradiated and 228 nonconditioned NOD/Scid mice. A high mortality was observed in irradiated but not in nonconditioned recipients. More than 90% of analyzed implanted breast cancer specimens engrafted in the NOD/Scid mice irrespective of pretreatment. The tumors were vascularized within 3 days of implantation and maintained original histomorphology as well as expression patterns of tumor markers (cytokeratin and MUCI) and cytokines (tumor necrosis factor alpha (TNF-alpha), interleukin-4 (IL-4) and IL-10) released by adjacent stromal cells. A majority of tumors grew slowly, locally infiltrating host tissue, whereas some grew aggressively, developing large, fatal tumor masses and metastases within regional lymph nodes. Tumor progression in mice correlated with stage, grade, proliferation index and hormone receptor status of primary tumors. The reproducible growth behavior and preservation of characteristic features suggest that this new xenotransplant model is relevant and can be recommended for testing new anticancer therapies. (C) 2003 Wiley-Liss. Inc
    Type of Publication: Journal article published
    PubMed ID: 12712433
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  • 8
    Keywords: PEPTIDE ; APOPTOSIS ; CANCER ; CELLS ; tumor ; TUMOR-CELLS ; CELL ; Germany ; human ; IN-VIVO ; VIVO ; PROTEIN ; PROTEINS ; TISSUE ; TUMORS ; MICE ; PATIENT ; LIGAND ; REDUCTION ; INDUCTION ; TISSUES ; ANTIGEN ; ANTIGENS ; DENDRITIC CELLS ; SKIN ; T cell ; T cells ; T-CELL ; T-CELLS ; bone marrow ; BONE-MARROW ; BREAST ; breast cancer ; BREAST-CANCER ; IMMUNE-RESPONSES ; MEMORY ; NOD/Scid mice ; RECOGNITION ; GLYCOPROTEIN ; PEPTIDES ; PHENOTYPE ; CANCER-PATIENTS ; CD8(+) ; P-SELECTIN ; REJECTION ; NAIVE ; CANCER PATIENTS ; TUMOR CELLS ; EFFECTOR ; CLUSTER ; SCID MICE ; TUMOR-ASSOCIATED ANTIGENS ; AUTOLOGOUS TUMOR ; breast tumors ; homing ; IMMUNOLOGICAL MEMORY ; INFILTRATION ; PROGRAM ; SELECTIN LIGANDS ; SUBSET
    Abstract: Bone marrow of breast cancer patients was found to contain CD8(+) T cells specific for peptides derived from breast cancer-associated proteins MUC1 and Her-2/neu. Most of these cells had a central or effector memory phenotype (CD45RA(-)CD62L(+) or CD45RA(-)CD62L(-), respectively). To test their in vivo function, we separated bone marrow-derived CD45RA(+) naive or CD45RA(-)CD45RO(+) memory T cells, stimulated them with autologous dendritic cells pulsed with tumor lysate, and transferred them into NOD/SCID mice bearing autologous breast tumors and normal skin transplants. CD45RA(-) memory but not CD45RA(+) naive T cells infiltrated autologous tumor but not skin tissues after the transfer. These tumor-infiltrating cells had a central or effector memory phenotype and produced perforin. Many of them expressed the beta-selectin glycoprotein ligand 1 and were found around beta-selectin(+) tumor endothelium. Tumor infiltration included cluster formation in tumor tissue by memory T cells with cotransferred dendritic cells. It was associated with the induction of tumor cell apoptosis and significant: tumor reduction. We thus demonstrate selective homing of memory T cells to human tumors and suggest that tumor rejection is based on the recognition of tumor-associated antigens on tumor cells and dendritic cells by autologous specifically activated central and effector memory T cells
    Type of Publication: Journal article published
    PubMed ID: 15232613
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  • 9
    Keywords: PEPTIDE ; CELLS ; tumor ; TUMOR-CELLS ; BLOOD ; Germany ; THERAPY ; GENERATION ; LINES ; MICE ; PATIENT ; RESPONSES ; IFN-GAMMA ; ENRICHMENT ; ANTIGEN ; DENDRITIC CELLS ; T-CELLS ; CELL-LINES ; FREQUENCY ; bone marrow ; BONE-MARROW ; MALIGNANCIES ; LINE ; LYMPHOCYTES ; EPITOPES ; INTERFERON ; PERIPHERAL-BLOOD ; HEALTHY ; cell lines ; HEMATOLOGIC MALIGNANCIES ; CTL ; INTERFERON-GAMMA ; MULTIPLE-MYELOMA ; CYTOTOXICITY ; multiple myeloma ; MALIGNANCY ; RE ; secretion ; BM ; memory T cells
    Abstract: Multiple myeloma (MM) is one of the most common hematologic malignancies. Despite extensive therapeutical approaches, cures remain rare exceptions. An important issue for future immunologic treatments is the characterization of appropriate tumor-associated antigens. Recently, a highly glycosylated mucin MUC1 was detected on a majority of multiple myeloma cell lines. We analyzed bone marrow and peripheral blood of 68 patients with HLA-A2-positive myeloma for the presence and functional activity of CD8 T cells specific for the MUC1-derived peptide LLLLTVLTV. Forty-four percent of the patients with MM contained elevated frequencies of MUC1-specific CD8 T cells in freshly isolated samples from peripheral blood (PB) or bone marrow (BM) compared with corresponding samples from healthy donors. BM-residing T cells possessed a higher functional capacity upon specific reactivation than PB-derived T cells with regard to interferon gamma (IFN-gamma) secretion, perforin production, and cytotoxicity. (C) 2005 by The American Society of Hematology
    Type of Publication: Journal article published
    PubMed ID: 15561890
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  • 10
    Keywords: CANCER ; CELLS ; EXPRESSION ; tumor ; BLOOD ; carcinoma ; CELL ; Germany ; QUANTIFICATION ; TISSUE ; TIME ; PATIENT ; ACTIVATION ; RESPONSES ; IFN-GAMMA ; prognosis ; ANTIGEN ; T cell ; T cells ; T-CELL ; T-CELLS ; MOLECULE ; bone marrow ; BONE-MARROW ; BREAST-CANCER ; IMMUNE-RESPONSES ; STAGE ; IN-SITU ; immunohistochemistry ; NUMBER ; colorectal cancer ; COLORECTAL-CANCER ; LYMPHOCYTES ; microsatellite instability ; MIGRATION ; CANCER-PATIENTS ; IMMUNE-RESPONSE ; T-LYMPHOCYTES ; FLUORESCENCE ; CANCER PATIENTS ; T lymphocytes ; INFILTRATION ; PROGNOSTIC-FACTOR ; IMMUNE-SYSTEM ; TUMOR TISSUE ; T helper cell ; correlation ; T helper cells ; BONE ; CD8(+) T cell ; immune responses ; CELL RESPONSE
    Abstract: Objective: To examine whether tumor-selective infiltration, activation, and cytotoxic activity of tumor infiltrating T lymphocytes (TIL) can be demonstrated in situ in colorectal cancer samples. Summary Background Data: Recent studies indicated a correlation between the presence of TIL and an improved prognosis in colorectal cancer. However, tumor-selective activation and cytotoxic activity of CD8(+) TIL in situ in colorectal cancer patients have not yet been examined. Methods: Tumor samples from 49 patients and corresponding normal mucosa samples from 23 patients with colorectal cancer (UICC stages II-IV) were examined for TIL. Two-color fluorescence immunohistochemistry and multicolor flowcytometric (FACS) analysis were used for quantification of CD8(+) T cells and measurement of their activation status (CD69-expression) and cytotoxic activity (CD107a-expression) in situ. Presence of tumor antigen-reactive T cells in tumor, blood, and bone marrow was evaluated by IFN-gamma Elispot analysis. Results: While absolute numbers of CD8(+) T cells were similar, CD4(+) T helper cells were significantly increased in tumor tissue compared with normal mucosa. There was a significantly higher proportion of activated and cytotoxically active CD8(+) TIL in colorectal cancer compared with normal mucosa. Increased activation, cytotoxic activity, and functional reactivity of TIL were correlated with the presence of functional tumor antigen-reactive T cells in the blood and bone marrow. The proportion of activated TIL decreased significantly with higher tumor stage. Conclusions: Tumor-selective activation and cytotoxic activity of CD8(+) TIL and tumor-selective migration of CD4(+) T helper cells were demonstrated in colorectal cancer for the first time. Our data support the immunogenicity of colorectal cancer and suggest clinical significance of tumor-specific immune responses
    Type of Publication: Journal article published
    PubMed ID: 17122624
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