Immune surveillance against a solid tumor fails because of immunological ignorance.
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Many peripheral solid tumors such as sarcomas and carcinomas express tumor-specific antigens that can serve as targets for immune effector T cells. Nevertheless, overall immune surveillance against such tumors seems relatively inefficient. We studied immune surveillance against a s.c. sarcoma expressing a characterized viral tumor antigen. Surprisingly, the tumor cells were capable of inducing a protective cytotoxic T cell response if transferred as a single-cell suspension. However, if they were transplanted as small tumor pieces, tumors readily grew. Tumor growth correlated strictly with (i) failure of tumor cells to reach the draining lymph nodes and (ii) absence of primed cytotoxic T cells. Cytotoxic T cells were not tolerant or deleted because a tumor antigen-specific cytotoxic T cell response was readily induced in lymphoid tissue by immunization with virus or with tumor cells even in the presence of large tumors. Established tumors were rejected by vaccine-induced effector T cells if effector T cells were maintained by prolonged or repetitive vaccination, but not by single-dose vaccination. Thus, in addition to several other tumor-promoting parameters, some antigenic peripheral sarcomas-and probably carcinomas-may grow not because they anergize or tolerize tumor-specific T cells, but because such tumors are immunologically dealt with as if they were in a so-called immunologically privileged site and are ignored for too long. (+info)
Evidence for involvement of B lymphocytes in the surveillance of lung metastasis in the rat.
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These studies examined the composition of lymphocytes within the lung after the introduction of tumor cells that metastasize to the lung in rats. i.v. delivery of MADB106 tumor cells into syngeneic Fischer 344 rats caused dose- and time-dependent development of lung tumors, with surface metastases evident 7 days after injection and markedly increased 11 days after injection. The total number of lymphocytes recovered from the lung was increased 11 days after injection but not 7 days after injection. When lymphocytes from the lung, spleen, and blood were subjected to fluorescence-activated cell sorting analysis, the most conspicuous change was an increase in the percentage of CD45RA+ cells (i.e., B lymphocytes in the rat) in the lung, with no changes seen in the percentage of natural killer (NKR-P1+), CD4+, or CD8+ cells in the lung. Analysis of the time course showed that B lymphocytes increased in the lung soon after i.v. tumor injection, with an initial peak seen 6 h after injection. Rapid influx of B lymphocytes into lung after i.v. tumor cell injection was also observed in another syngeneic tumor model, i.e., after injection of CC531 cells into WAG rats. To determine whether the influx of B lymphocytes into the lung might participate in tumor surveillance, a high dose of antibody (100 microg) to rat B lymphocytes was given to immunoneutralize these cells; this produced an increase in lung tumors in both models. Finally, Fischer 344 rats were given a s.c. injection of MADB106 tumor cells that made them resistant to lung tumors when given a later i.v. injection of these tumor cells. These animals were found to have an elevated level of B lymphocytes residing in the lung associated with the resistance to lung tumor. These findings suggest that early responses of B lymphocytes are important in protection against tumor development in two rat models of cancer. (+info)
Loss of HLA haplotype in lung cancer cell lines: implications for immunosurveillance of altered HLA class I/II phenotypes in lung cancer.
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Loss of expression of HLA class I antigens has been demonstrated in a wide variety of tumors and is considered to be one of the mechanisms whereby tumors escape T-cell surveillance. Genomic DNA of MHC class I/II molecules in seven lung cancer cell lines was investigated and compared with that in peripheral blood mononuclear cells. In three cell lines, OU-LC-A1, OU-LC-A2, and OU-LC-AS1, a loss of HLA haplotype was observed. Aberrations of HLA class I/II in tumor cell lines should be considered when MHC-restricted phenomena in vitro models are assessed and clinical use of tumor vaccination in vivo is considered. (+info)
Overexpression of sialomucin complex, a rat homologue of MUC4, inhibits tumor killing by lymphokine-activated killer cells.
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Sialomucin complex (SMC) is a large heterodimeric glycoprotein complex composed of a mucin subunit ascites sialoglycoprotein-1 and a transmembrane subunit ascites sialoglycoprotein-2. It is a rat homologue of human mucin gene MUC4 and is abundantly expressed on the cell surface of highly metastatic ascites 13762 rat mammary adenocarcinoma cells. Because of their extended and rigid structures, mucin-type glycoproteins are suggested to have suppressing effects on cell-cell and cell-matrix interactions. During the metastatic process, these effects presumably cause tumor cell detachment from the primary tumor mass and facilitate escape of the tumor cells from immunosurveillance. Analyses of human breast cancer cells in solid tumors and tumor effusions showed that the more aggressive cells in effusions are stained with polyclonal antibodies against SMC more frequently than cells in solid tumors, suggesting a role for MUC4/SMC in tumor progression and metastasis. Previously, we generated recombinant cDNAs for SMC that vary in the number of mucin repeats to study the putative functions of SMC in tumor metastasis. These cDNAs were transfected into human cancer cell lines and tested for the effect of the expression of this gene. Here, using a tetracycline-responsive inducible expression system, we demonstrate that overexpression of SMC masks the surface antigens on target tumor cells and effectively suppresses tumor cell killing by cytotoxic lymphocytes. This effect results from the ability of SMC to block killer cell binding to the tumor cells and is dependent on both overexpression of the mucin and the number of mucin repeats in the expressed SMC. These results provide an explanation for the proposed role of SMC/MUC4 in tumor progression. (+info)
Low prevalence of selective human leukocyte antigen (HLA)-A and HLA-B epitope losses in early-passage tumor cell lines.
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The down-regulation of human leukocyte antigen (HLA) class I molecules, especially the selective down-regulation of certain allelic products, is believed to represent a major mechanism of tumor escape from immune surveillance. In the present report, an original approach is described to precisely evaluate and classify HLA class I epitope losses in 30 cancer patients with malignant melanoma and lung, breast, endometrium, ovary, and colon carcinoma tumors. Early-passage tumor cell lines were established in culture from the corresponding metastatic tumor lesions obtained in each patient. Both the cell lines and the tumor lesions were compared, in their HLA-A and -B expression, to the peripheral blood mononuclear cells (PBMCs) obtained from the same patient (autologous PBMCs). On the basis of HLA-genotyping data, the appropriate monoclonal antibodies identifying mono- and poly-morphic HLA-A and HLA-B epitopes were selected from a panel of 34 antibodies for a total of 24 testable alleles. The selected antibodies were used not only in immunohistochemical assays on cryostatic tumor sections and cytospins of PBMCs but also in quantitative, sensitive flow cytometry assays on early-passage tumor cells and PBMC suspensions. With this latter method, a low overall HLA expression was detected in 26 tumor cell explants and a complete, generalized HLA-A, HLA-B, HLA-C loss in the remaining 4 cases. However, no complete, selective loss of any of the 45 tested HLA-A and HLA-B allomorphs was observed. Sequences from all of the HLA class I alleles could be detected at the genomic DNA level in tumor cells and tissues. At variance from the literature and the results of immunohistochemical experiments performed in parallel on the corresponding tumor lesions, the relative proportions of the various HLA epitopes were relatively preserved in each early-passage cell line/PBMC pair, and selective increases, rather than decreases, in the expression of polymorphic HLA epitopes had the highest prevalence and greatest magnitude. Our data suggest an alternative tumor stealth strategy in which up- and down-regulation are equally important. This alternative model of tumor-host interaction better fits the available models of tumor cell recognition by CTLs and natural killer cells bearing activatory and inhibitory receptors for HLA-A, HLA-B, HLA-C molecules. (+info)
A model for CD8+ CTL tumor immunosurveillance and regulation of tumor escape by CD4 T cells through an effect on quality of CTL.
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Understanding immune mechanisms influencing cancer regression, recurrence, and metastasis may be critical to developing effective immunotherapy. Using a tumor expressing HIV gp160 as a model viral tumor Ag, we found a growth-regression-recurrence pattern, and used this to investigate mechanisms of immunosurveillance. Regression was dependent on CD8 T cells, and recurrent tumors were resistant to CTL, had substantially reduced expression of epitope mRNA, but retained the gp160 gene, MHC, and processing apparatus. Increasing CTL numbers by advance priming with vaccinia virus expressing gp160 prevented only the initial tumor growth but not the later appearance of escape variants. Unexpectedly, CD4 cell depletion protected mice from tumor recurrence, whereas IL-4 knockout mice, deficient in Th2 cells, did not show this protection, and IFN-gamma knockout mice were more susceptible. Purified CD8 T cells from CD4-depleted mice following tumor regression had more IFN-gamma mRNA and lysed tumor cells without stimulation ex vivo, in contrast to CD4-intact mice. Thus, the quality as well as quantity of CD8+ CTL determines the completeness of immunosurveillance and is controlled by CD4 T cells but not solely Th2 cytokines. This model of immunosurveillance may indicate ways to enhance the efficacy of surveillance and improve immunotherapy. (+info)
Positive selection of natural autoreactive B cells.
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Lymphocyte development is critically influenced by self-antigens. T cells are subject to both positive and negative selection, depending on their degree of self-reactivity. Although B cells are subject to negative selection, it has been difficult to test whether self-antigen plays any positive role in B cell development. A murine model system of naturally generated autoreactive B cells with a germ line gene-encoded specificity for the Thy-1 (CD90) glycoprotein was developed, in which the presence of self-antigen promotes B cell accumulation and serum autoantibody secretion. Thus, B cells can be subject to positive selection, generated, and maintained on the basis of their autoreactivity. (+info)
An expanded peripheral T cell population to a cytotoxic T lymphocyte (CTL)-defined, melanocyte-specific antigen in metastatic melanoma patients impacts on generation of peptide-specific CTLs but does not overcome tumor escape from immune surveillance in metastatic lesions.
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It is not known if immune response to T cell-defined human histocompatibility leukocyte antigen (HLA) class I-restricted melanoma antigens leads to an expanded peripheral pool of T cells in all patients, affects cytotoxic T lymphocyte (CTL) generation, and correlates with anti-tumor response in metastatic lesions. To this end, a limiting dilution analysis technique was developed that allowed us to evaluate the same frequency of peptide-specific T cells as by staining T cells with HLA-peptide tetrameric complexes. In four out of nine patients, Melan-A/Mart-1(27-35)-specific CTL precursors (CTLp) were >/=1/2,000 peripheral blood lymphocytes and found mostly or only in the CD45RO(+) memory T cell subset. In the remaining five patients, a low (<1/40,000) peptide-specific CTLp frequency was measured, and the precursors were only in the CD45RA(+) naive T cell subset. Evaluation of CTL effector frequency after bulk culture indicated that peptide-specific CTLs could be activated in all patients by using professional antigen-presenting cells as dendritic cells, but CTLp frequency determined the kinetics of generation of specificity and the final number of effectors as evaluated by both limiting dilution analysis and staining with HLA-A*0201-Melan-A/Mart-1 tetrameric complexes. Immunohistochemical analysis of 26 neoplastic lesions from the nine patients indicated absence of tumor regression in most instances, even in patients with an expanded peripheral T cell pool to Melan-A/Mart-1 and whose neoplastic lesions contained a high frequency of tetramer-positive Melan-A/Mart-1-specific T cells. Furthermore, frequent lack of a "brisk" or "nonbrisk" CD3(+)CD8(+) T cell infiltrate or reduced/absent Melan-A/Mart-1 expression in several lesions and lack of HLA class I antigens were found in some instances. Thus, expansion of peripheral immune repertoire to Melan-A/Mart-1 takes place in some metastatic patients and leads to enhanced CTL induction after antigen-presenting cell-mediated selection, but, in most metastatic lesions, it does not overcome tumor escape from immune surveillance. (+info)