作者: Séverine Valmary-Degano ; Philippe Rochaix ; Talal al Saati ; Laurence Lamant ; Sophie Le Guellec ; Cécile Pagès ; Pierre Payoux ; François Launay ; Paul Carle ; Frédéric Lauwers ; Pierre Brousset ; Serge Boulinguez

We previously described a novel antimelanoma antibody, designated KBA.62. However, review of the literature showed that only a few studies have reported on this antibody. We report our experience in the diagnosis of melanoma using KBA.62 and its value in both primary and metastatic conditions. In addition to conventional melanomas, we included desmoplastic and spindle cell melanomas, whose diagnosis can be challenging. We also focus on identification of malignant cells in sentinel lymph node biopsies using KBA.62, by comparison with anti-S-100 protein and HMB-45 antibodies, because discrepancies in sensitivity and specificity of melanoma markers have given rise to numerous studies aiming to determine the best panel for the evaluation of sentinel lymph node from patients with melanoma. Overall, KBA.62 was positive in 93% of primary and metastatic melanomas. Interestingly, the 12 cases of desmoplastic and spindle cell melanomas had strongly positive results. In addition, the results of our study performed on a series of 215 sentinel lymph nodes showed that the sensitivity of anti-S-100 protein and KBA.62 antibodies in detecting occult metastasis was similar. Moreover, KBA.62 identified 6 patients (3%) who had confirmed sentinel lymph node metastasis but were negative for HMB-45. The resolution was higher with KBA.62 than that observed with anti-S-100 protein antibody, as the nonmelanocytic positive cells for KBA.62 in lymph nodes were only represented by endothelial cells, which therefore constituted an intrinsic positive control. We conclude that KBA.62 antibody is a useful additional marker for melanoma, specifically in desmoplastic/spindle cell cases and in the context of micrometastasis in sentinel lymph node.

2003-06-01·Cancer research

Fourteenth Annual Pezcoller Symposium: the novel dichotomy of immune interactions with tumors.

作者: Lanzavecchia, Antonio ; Hanahan, Douglas ; Mihich, Enrico

The main focus of the Symposium was the fact that cell types of the innate and adaptive immune systems can have tumor-favoring as well as tumor antagonistic effects, both in a preventive and therapeutic mode. It was shown that macrophages (Mphi) and dendritic cells within a tumor exert tumor-favoring effects through the action of certain cytokines. Inflammatory reactions could favor the onset and growth of tumors. Dual immune functions were shown with CD4+ T cells and certain matrix metalloproteinase (MMP) activities favoring tumor progression and CD8+ T cells and certain heat shock proteins having antitumor action. Lack of antitumor action despite positive immune stimulation was also shown to depend on the existence of barriers to tumor infiltration by lymphocytes; remodeling of vasculature, e.g., by IFNgamma-induced cytokines like MIG and IPIO, reversed this type of impediment. Certain CXC cytokines increased tumor progression, whereas others, particularly those induced by IFNgamma, had the opposite effect; stromal-derived factor-1 and its receptor CXCR4 affected tumor propensity to metastasize in certain organs. Stromal-derived factor-1 induced MMP9, which in turn regulated the bioavailability of vascular endothelial growth factor and the cascade of its tumor-favoring effects, whereas granulocyte colony-stimulating factor decreased MMP9 and the consequences of its action. The effects of certain proinflammatory cytokines and vascular endothelial growth factor functions in angiogenesis and lymphoangiogenesis were also discussed. The favoring effects of fever-like thermal stress on the function of molecules instrumental in lymphoid cell adhesion to vessels and infiltration into sites of immune actions were described. The mechanisms involved in the development of immune memory and those conditioning Type I and CTL responses were also discussed. A number of presentations were concerned with laboratory studies aimed at developing clinical regimens with potential activity in the prevention or treatment of cancer. Prevention of Her2/neu breast cancer in transgenic mice was achieved by suitable regimens with IL12 combined with vaccines, including DNA-based vaccines administered in conjunction with electroporation. Vaccination with shared tumor antigen MUCI or cyclin B was discussed, and its clinical translation was described. The prevention of TRAMP prostate tumor in transgenic mice by anti-CTLA4 antibody plus vaccine was described, as was the translation of these regimens to the clinics. Clinical successes in melanoma patients using antimelanoma antigen antibodies in a therapeutic mode and precautions to be exerted in evaluating in vivo immune responses based on in vitro assays were emphasized. The symposium was concluded with an overall discussion focused on basic questions related to the capability of immunity to exert tumor-favoring or antitumor effects depending on conditions determined by both tumor and host functions.

2002-05-14·Proceedings of the National Academy of Sciences1区 · 综合性期刊

ATP6S1 elicits potent humoral responses associated with immune-mediated tumor destruction

1区 · 综合性期刊

Article

作者: Mihm, Martin ; Soiffer, Robert J. ; Alyea, Edwin P. ; Dranoff, Glenn ; Hodi, F. Stephen ; Neuberg, Donna ; Lynch, Thomas ; Yang, Jihong ; Salgia, Ravi ; Ritz, Jerome ; Schmollinger, Jan C.

An important goal of cancer immunology is the identification of antigens associated with tumor destruction. Vaccination with irradiated tumor cells engineered to secrete granulocyte/macrophage colony-stimulating factor (GM-CSF) generates potent, specific, and long-lasting antitumor immunity in multiple murine tumor models. A phase I clinical trial of this vaccination strategy in patients with advanced melanoma demonstrated the consistent induction of dense CD4 + and CD8 + T lymphocyte and plasma cell infiltrates in distant metastases, resulting in extensive tumor destruction, fibrosis, and edema. Antimelanoma antibody and cytotoxic T cell responses were associated with tumor cell death. To characterize the targets of these responses, we screened an autologous cDNA expression library prepared from a densely infiltrated metastasis with postvaccination sera from a long-term responding patient. High-titer IgG antibodies detected ATP6S1, a putative accessory unit of the vacuolar H + –ATPase complex. A longitudinal analysis of this patient revealed an association between the vaccine-induced increase in antibodies to ATP6S1 and tumor destruction. Three additional vaccinated melanoma patients and three metastatic non-small cell lung carcinoma patients vaccinated with autologous GM-CSF-secreting tumor cells similarly showed a correlation between humoral responses to ATP6S1 and tumor destruction. Moreover, a chronic myelogenous leukemia patient who experienced a complete remission after CD4 + donor lymphocyte infusions also developed high-titer antibodies to ATP6S1. Lastly, vaccination with GM-CSF-secreting B16 melanoma cells stimulated high-titer antibodies to ATPS1 in a murine model. Taken together, these findings demonstrate that potent humoral responses to ATP6S1 are associated with immune-mediated destruction of diverse tumors.

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