How much longer will tumour cells fool the immune system?

Ferrone, Soldano; Finerty, John F.; Jaffee, Elizabeth M.; Nabel, Gary J.

doi:10.1016/s0167-5699(99)01569-8

Cited by 38 publications

(25 citation statements)

References 5 publications

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“…Neoplastic cells may evade cell-mediated immunity at multiple levels of the effector/target interaction (37)(38)(39)(40)(41)(42), which consequently may impact the malignant process. Tumor escape mechanisms may affect Ag recognition, conjugate formation, or T cell activation or proliferation.…”

Section: Discussionmentioning

confidence: 99%

Exposure of Human Primary Colon Carcinoma Cells to Anti-Fas Interactions Influences the Emergence of Pre-existing Fas-Resistant Metastatic Subpopulations

Liu

McDuffie

Abrams

2003

The Journal of Immunology

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Fas, an important death receptor-mediated signaling pathway, has been shown to be down-regulated during human colon tumorigenesis; however, how alterations in Fas expression influence the metastatic process remains unresolved. In mouse models, loss of Fas function was found to be both necessary and sufficient for tumor progression. In this study, we investigated the link between functional Fas status and malignant phenotype using a matched pair of naturally occurring primary (Fas-sensitive) and metastatic (Fas-resistant) human colon carcinoma cell lines in both in vitro and in vivo (xenograft) settings. Metastatic sublines were produced in vitro from the primary tumor cell line by functional elimination of Fas-responsive cells. Conversely, sublines derived from the primary tumor in vivo at distal metastatic sites were Fas-resistant. In contrast, simply disrupting the Fas pathway by molecular-based strategies in the Fas-sensitive primary tumor failed to achieve the same metastatic outcome. Interestingly, both in vitro- and in vivo-produced sublines resembled the naturally occurring metastatic population, based on functional and morphologic studies and genome-scale gene expression profiling. Overall, using this human colon carcinoma model, we: 1) showed that loss of Fas function was linked to, but alone was insufficient for, acquisition of a detectable metastatic phenotype; 2) demonstrated that metastatic subpopulations pre-existed within the heterogeneous primary tumor, and that anti-Fas interactions served as a selective pressure for their outgrowth; and 3) identified a large set of differentially expressed genes distinguishing the primary from metastatic malignant phenotypes. Thus, Fas-based interactions may represent a novel mechanism for the biologic or immunologic selection of certain types of Fas-resistant neoplastic clones with enhanced metastatic ability.

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Section: Discussionmentioning

confidence: 99%

Exposure of Human Primary Colon Carcinoma Cells to Anti-Fas Interactions Influences the Emergence of Pre-existing Fas-Resistant Metastatic Subpopulations

Liu

McDuffie

Abrams

2003

The Journal of Immunology

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“…It is caused by a wide variety of suggested mechanisms, such as the production of suppressive cytokines, loss of immunodominant peptides, resistance to killing mechanisms (apoptosis), and loss/ downregulation of class I MHC (1)(2)(3)(4). HLA loss can result from a number of different mutations, loss of b-2-microglobulin, TAP1/TAP2 mutations, loss of heterozygosity in the MHC genes, and downregulation of specific MHC alleles (5,6).…”

Section: Introductionmentioning

confidence: 99%

Recruitment of Oligoclonal Viral-Specific T cells to Kill Human Tumor Cells Using Single-Chain Antibody–Peptide–HLA Fusion Molecules

Noy

Haus-Cohen

Oved

et al. 2015

Molecular Cancer Therapeutics

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Tumor progression is often associated with the development of diverse immune escape mechanisms. One of the main tumor escape mechanism is HLA loss, in which human solid tumors exhibit alterations in HLA expression. Moreover, tumors that present immunogenic peptides via class I MHC molecules are not susceptible to CTL-mediated lysis, because of the relatively low potency of the tumor-specific CLTs. Here, we present a novel cancer immunotherapy approach that overcomes these problems by using the high affinity and specificity of antitumor antibodies to recruit potent antiviral memory CTLs to attack tumor cells. We constructed a recombinant molecule by genetic fusion of a cytomegalovirus (CMV)-derived peptide pp65 (NLVPMVATV) to scHLA-A2 molecules that were genetically fused to a single-chain Fv Ab fragment specific for the tumor cell surface antigen mesothelin. This fully covalent fusion molecule was expressed in E. coli as inclusion bodies and refolded in vitro. The fusion molecules could specifically bind mesothelin-expressing cells and mediate their lysis by NLVPMVATV-specific HLA-A2-restricted human CTLs. More importantly, these molecules exhibited very potent antitumor activity in vivo in a nude mouse model bearing preestablished human tumor xenografts that were adoptively transferred along with human memory CTLs. These results represent a novel and powerful approach to immunotherapy for solid tumors, as demonstrated by the ability of the CMV-scHLA-A2-SS1(scFv) fusion molecule to mediate specific and efficient recruitment of CMV-specific CTLs to kill tumor cells.

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“…Accordingly, it has been shown that autologous dendritic cells (DC) 3 pulsed with peptides specific for prostate-specific Ag (PSA) (1), prostate-specific membrane Ag (2), or telomerase reverse transcriptase (TERT) (3) are capable of stimulating potent CTL in vitro, suggesting their role as potential candidate Ags for prostate cancer immunotherapy. Nonetheless, there is growing recognition that there may be significant advantages to inducing immune responses against a broad spectrum of Ags expressed by the patient's autologous tumor, rather than targeting single, defined tumor Ags (4,5). Recent research indicates that the emergence of Ag loss mutants frequently arising at metastatic sites may render a substantial proportion of tumors resistant to single Ag-specific immunotherapy (6 -8).…”

mentioning

confidence: 99%

Induction of Polyclonal Prostate Cancer-Specific CTL Using Dendritic Cells Transfected with Amplified Tumor RNA

Heiser

Maurice

Yancey

et al. 2001

The Journal of Immunology

183

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Polyvalent cancer vaccines targeting the entire antigenic spectrum on tumor cells may represent a superior therapeutic strategy for cancer patients than vaccines solely directed against single Ags. In this study, we show that autologous dendritic cells (DC) transfected with RNA amplified from microdissected tumor cells are capable of stimulating CTL against a broad set of unidentified and critical prostate-specific Ags. Although the polyclonal CTL responses generated with amplified tumor RNA-transfected DC encompassed as a subcomponent a response against prostate-specific Ag (PSA) as well as against telomerase reverse transcriptase, the tumor-specific CTL were consistently more effective than PSA or telomerase reverse transcriptase CTL to lyse tumor targets, suggesting the superiority of the polyclonal response. Although tumor RNA-transfected DC stimulated CTL, which recognized not only tumor but also self-Ags expressed by benign prostate tissue, these cross-reactive CTL were exclusively specific for the PSA, indicating an immunodominant role of PSA in the prostate cancer-specific immune response. Our data suggest that tumor RNA-transfected DC may represent a broadly applicable, potentially clinically effective vaccine strategy for prostate cancer patients, which is not limited by tumor tissue availability for Ag preparation and may minimize the risk of clonal tumor escape.

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How much longer will tumour cells fool the immune system?

Cited by 38 publications

References 5 publications

Exposure of Human Primary Colon Carcinoma Cells to Anti-Fas Interactions Influences the Emergence of Pre-existing Fas-Resistant Metastatic Subpopulations

Exposure of Human Primary Colon Carcinoma Cells to Anti-Fas Interactions Influences the Emergence of Pre-existing Fas-Resistant Metastatic Subpopulations

Recruitment of Oligoclonal Viral-Specific T cells to Kill Human Tumor Cells Using Single-Chain Antibody–Peptide–HLA Fusion Molecules

Induction of Polyclonal Prostate Cancer-Specific CTL Using Dendritic Cells Transfected with Amplified Tumor RNA

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