MHC‐restricted responses of CD8<sup>+</sup> AND CD4<sup>+</sup> T‐cell clones from regional lymph nodes of melanoma patients

Chen, Qiyuan; Hersey, Peter

doi:10.1002/ijc.2910510209

Cited by 39 publications

(12 citation statements)

References 27 publications

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“…The latter studies suggest that CD4 T cells may exert direct cytotoxic effects on melanoma cells separate from their helper effects on CD8 CTLs. This is supported by several studies showing that CD4 T cells mediate direct lytic effects on melanoma cells in vitro (Chen and Hersey, 1992;Takahashi et al, 1995) and that an epitope in tyrosinase is one of the antigens recognized by CD4 T cells (Topalian et al, 1996).…”

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confidence: 70%

CD4 T cells kill melanoma cells by mechanisms that are independent of Fas (CD95)

Thomas

Hersey

1998

Int. J. Cancer

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Previous studies have shown that CD4 T cells are associated with regression in primary melanoma and rejection of tumors in adoptive transfer models. The mechanism by which they mediate their anti‐tumor effects remains unclear, and some studies have suggested that Fas ligand (FasL)/Fas interactions were involved. In the present study, we have examined the cytotoxic mechanism involved in CD4 T‐cell killing of melanoma cells and, in particular, the role of FasL/Fas interactions in this killing. We show that the CD4 T cells in 4 clones of T cells induced apoptosis in autologous melanoma cells by MHC‐restricted mechanisms but lysed an allogeneic melanoma cell by a non‐apoptotic mechanism. Melanoma cells expressed both Fas and FasL, but killing of melanoma cells did not involve Fas/FasL interactions. This was shown by a lack of correlation between Fas expression and susceptibility to lysis and by failure of a monoclonal antibody to Fas to block killing by the CD4 T cells, though the latter expressed FasL. Recombinant FasL did not induce killing of melanoma cells. Int. J. Cancer 75:384–390, 1998. © 1998 Wiley‐Liss, Inc.

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confidence: 70%

CD4 T cells kill melanoma cells by mechanisms that are independent of Fas (CD95)

Thomas

Hersey

1998

Int. J. Cancer

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“…Although experimental immunization strategies for patients with melanoma and other cancers currently emphasize shared class I-restricted tumor antigens recognized by CD8+ T cells, immunization against both class I-and class II-restricted epitopes may increase the effectiveness of these approaches. Previous reports suggesting the presence of shared MHC class II-restricted melanoma antigens have measured direct T-cell-tumor cell interactions and were thus limited by the extensive polymorphism of human class II molecules and reagent availability (39)(40)(41)(42). However, as demonstrated here, a bioassay which utilizes one APC for multiple sources of antigen will permit rapid screening and detection of shared CD4-recognized tumor antigens.…”

Section: Methodsmentioning

confidence: 92%

Human CD4+ T cells specifically recognize a shared melanoma-associated antigen encoded by the tyrosinase gene.

Topalian

Rivoltini

Mancini

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

244

101

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Although commonly expressed human melanoma-associated antigens r g d by CD8+ cytolytic T cells have been described, little is known about CD4+ T-cell recognition of melanoma-aated antigens. Epstein-Barr virustransformed B cells were used to present antigens derived from whole cell lysates of autologous and allogeneic melanomas for recognition by melanoma-specific CD4+ T-cell lines and clones cultured from tumor-infiltrating lymphocytes. HLA-DRrestricted antigens were detected in the lysates on the basis of specific release of cytokines from the responding T cells. Antigen sharing was demonstrated in the majority of melanomas tested, as well as in cultured normal melanocytes, but not in other normal tissues or nonmelanoma tumors. T-cell clones manifested a single recognition pattern, suggesting the presence of an immunodominant epitope. This epitope was identified as a product of the tyrosinase gene, which has also been shown to encode class I-restricted epitopes recognized by CD8+ T cells from melanoma patients. Identification of commonly expressed tumor-associated protein molecules containing epitopes presented by both class I and class H major histocompatibility molecules may provide optimal reagents for cancer immunization strategies.Commonly expressed melanoma-associated antigens can be recognized by CD8+ cytotoxic T lymphocytes (CTLs) derived from melanoma patients. In short-term lysis assays, CTLs grown from in vitro sensitized peripheral blood lymphocytes (PBLs) or lymph node lymphocytes or from lymphocytes infiltrating metastatic melanoma lesions have been shown to recognize autologous and major histocompatibility complex (MHC) class I-compatible allogeneic melanomas but not HLA-matched nonmelanoma tumors, lymphoblasts, or cultured fibroblasts (1, 2). Similar recognition patterns have been observed by measuring cytokine secretion from tumor infiltrating lymphocytes (TILs) cocultivated with autologous or HLA-matched allogeneic tumor stimulators (3). Expression of shared melanoma antigens even in tumors of discrepant HLA phenotypes has been shown by genetically modifying these tumors to express the HLA-A2.1 molecule: HLA-A2-restricted melanoma-specific CTLs lysed the majority of gene-modified melanomas tested, but not HLA-A2+ nonmelanoma tumors or normal tissues (4, 5). Recently, melanoma-specific HLA-A2-restricted CTL clones have been shown to recognize cultured normal melanocytes as well as their malignant counterparts, suggesting that shared melanoma antigens may be lineage specific (6). The multiplicity of melanoma-associated antigens present within isolated melanoma lesions, and even within individual melanoma cells, has been suggested on the cellular level (7, 8) and confirmed on the peptide level (9, 10). Five MHC class I-restricted melanoma-associated antigens have been molecularly defined (11)(12)(13)(14)(15)(16), encoding only a subset of these commonly expressed antigens. Therapeutic vaccination strategies are evolving based on these CD8-recognized epitopes.While animal models of maligna...

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“…However, high background activities and wide variability among replicate samples sometimes make these assays difficult to interpret. Several recent reports have shown the feasibility of using prolonged (12)(13)(14)(15)(16)(17)(18) h) 51Cr release assays to assess CD4+ T cell responses to autologous melanoma cells. '12,14,22' Paradoxically, two studies have shown that cytolytic antimelanoma CD4+ cells are MHC class I restricted but not class II restricted.…”

Section: Assessment Ofallogeneic Melanoma Recognitionmentioning

confidence: 99%

Analysis of Cytokine Secretion by Melanoma-Specific CD4⁺T Lymphocytes

Markus

Rosenberg

Topalian

1995

Journal of Interferon & Cytokine Research

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Although specific antitumor immune reactivity has been documented extensively in CD8+ T cells derived from melanoma patients, relatively little is known about CD4+ T cell responses against melanoma. Tumor-infiltrating lymphocytes (TIL) cultured from metastatic lesions in five patients yielded cytolytic CD8+ T cells with specific activity against autologous and MHC class I-compatible allogeneic melanoma targets. In four of the five cases studied, CD4+ T cells purified from bulk TIL cultures also reacted specifically with autologous melanoma cells, as manifested by the secretion of various cytokines (GM-CSF, TNF-alpha, and IFN-gamma) after a 24 h cocultivation. Cytokine secretion by CD4+ T cells was MHC class II restricted, and proved to be a more reliable indicator of the immunologic reactivity of CD4+ T cells than cytolysis. Three of the four reactive CD4+ TIL failed to recognize allogeneic melanomas, suggesting recognition of Ag with limited expression in the patient population. Cloning such Ags may provide clues to optimizing current antitumor immunization strategies.

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MHC‐restricted responses of CD8⁺ AND CD4⁺ T‐cell clones from regional lymph nodes of melanoma patients

Cited by 39 publications

References 27 publications

CD4 T cells kill melanoma cells by mechanisms that are independent of Fas (CD95)

CD4 T cells kill melanoma cells by mechanisms that are independent of Fas (CD95)

Human CD4+ T cells specifically recognize a shared melanoma-associated antigen encoded by the tyrosinase gene.

Analysis of Cytokine Secretion by Melanoma-Specific CD4⁺T Lymphocytes

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MHC‐restricted responses of CD8+ AND CD4+ T‐cell clones from regional lymph nodes of melanoma patients

Cited by 39 publications

References 27 publications

CD4 T cells kill melanoma cells by mechanisms that are independent of Fas (CD95)

CD4 T cells kill melanoma cells by mechanisms that are independent of Fas (CD95)

Human CD4+ T cells specifically recognize a shared melanoma-associated antigen encoded by the tyrosinase gene.

Analysis of Cytokine Secretion by Melanoma-Specific CD4+T Lymphocytes

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MHC‐restricted responses of CD8⁺ AND CD4⁺ T‐cell clones from regional lymph nodes of melanoma patients

Analysis of Cytokine Secretion by Melanoma-Specific CD4⁺T Lymphocytes