{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T05:00:24Z","timestamp":1791349224924,"version":"4.3.1"},"reference-count":44,"publisher":"Rockefeller University Press","issue":"3","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[1999,8,2]]},"abstract":"<jats:p>We examined the effectiveness of cytotoxic T lymphocyte\u2013associated antigen 4 (CTLA-4) blockade, alone or in combination with a granulocyte\/macrophage colony-stimulating factor (GM-CSF)\u2013expressing tumor cell vaccine, on rejection of the highly tumorigenic, poorly immunogenic murine melanoma B16-BL6. Recently established tumors could be eradicated in 80% (68\/85) of the cases using combination treatment, whereas each treatment by itself showed little or no effect. Tumor rejection was dependent on CD8+ and NK1.1+ cells but occurred irrespective of the presence of CD4+ T cells. Mice surviving a primary challenge rejected a secondary challenge with B16-BL6 or the parental B16-F0 line. The same treatment regimen was found to be therapeutically effective against outgrowth of preestablished B16-F10 lung metastases, inducing long-term survival. Of all mice surviving B16-BL6 or B16-F10 tumors after combination treatment, 56% (38\/68) developed depigmentation, starting at the site of vaccination or challenge and in most cases progressing to distant locations. Depigmentation was found to occur in CD4-depleted mice, strongly suggesting that the effect was mediated by CTLs. This study shows that CTLA-4 blockade provides a powerful tool to enhance T cell activation and memory against a poorly immunogenic spontaneous murine tumor and that this may involve recruitment of autoreactive T cells.<\/jats:p>","DOI":"10.1084\/jem.190.3.355","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T16:48:54Z","timestamp":1027702134000},"page":"355-366","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":886,"title":["Combination Immunotherapy of B16 Melanoma Using Anti\u2013Cytotoxic T Lymphocyte\u2013Associated Antigen 4 (Ctla-4) and Granulocyte\/Macrophage Colony-Stimulating Factor (Gm-Csf)-Producing Vaccines Induces Rejection of Subcutaneous and Metastatic Tumors Accompanied by Autoimmune Depigmentation"],"prefix":"10.1084","volume":"190","author":[{"given":"Andrea","family":"van Elsas","sequence":"first","affiliation":[{"name":"aFrom the Howard Hughes Medical Institute, Cancer Research Laboratory and Department of Molecular and Cellular Biology, University of California, Berkeley, California 94720-3200"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arthur A.","family":"Hurwitz","sequence":"additional","affiliation":[{"name":"aFrom the Howard Hughes Medical Institute, Cancer Research Laboratory and Department of Molecular and Cellular Biology, University of California, Berkeley, California 94720-3200"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James P.","family":"Allison","sequence":"additional","affiliation":[{"name":"aFrom the Howard Hughes Medical Institute, Cancer Research Laboratory and Department of Molecular and Cellular Biology, University of California, Berkeley, California 94720-3200"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[1999,8,2]]},"reference":[{"key":"2023072508500199500_R1","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1146\/annurev.iy.12.040194.002005","article-title":"Tumor antigens recognized by T lymphocytes","volume":"12","author":"Boon","year":"1994","journal-title":"Annu. 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Clin. Oncol."},{"key":"2023072508500199500_R35","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1097\/00002371-199601000-00009","article-title":"Vitiligo in patients with melanomanormal tissue antigens can be targets for cancer immunotherapy","volume":"19","author":"Rosenberg","year":"1996","journal-title":"J. Immunother. Emphasis Tumor Immunol."},{"key":"2023072508500199500_R36","doi-asserted-by":"crossref","first-page":"1034","DOI":"10.1046\/j.1523-1747.1998.00411.x","article-title":"Anti-tyrosinase-related protein-2 immune response in vitiligo patients and melanoma patients receiving active-specific immunotherapy","volume":"111","author":"Okamoto","year":"1998","journal-title":"J. Invest. Dermatol."},{"key":"2023072508500199500_R37","doi-asserted-by":"crossref","first-page":"1203","DOI":"10.1084\/jem.188.6.1203","article-title":"High frequency of skin-homing melanocyte-specific cytotoxic T lymphocytes in autoimmune vitiligo","volume":"188","author":"Ogg","year":"1998","journal-title":"J. Exp. Med."},{"key":"2023072508500199500_R38","doi-asserted-by":"crossref","first-page":"6458","DOI":"10.1073\/pnas.91.14.6458","article-title":"Identification of a human melanoma antigen recognized by tumor-infiltrating lymphocytes associated with in vivo tumor rejection","volume":"91","author":"Kawakami","year":"1994","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072508500199500_R39","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1084\/jem.185.3.453","article-title":"Identification of tyrosinase-related protein 2 as a tumor rejection antigen for the B16 melanoma","volume":"185","author":"Bloom","year":"1997","journal-title":"J. Exp. 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Med."},{"key":"2023072508500199500_R42","doi-asserted-by":"crossref","first-page":"2982","DOI":"10.1073\/pnas.96.6.2982","article-title":"Vaccination with a recombinant vaccinia virus encoding a \u201cself\u201d antigen induces autoimmune vitiligo and tumor cell destruction in micerequirement for CD4+ T lymphocytes","volume":"96","author":"Overwijk","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072508500199500_R43","doi-asserted-by":"crossref","first-page":"1258","DOI":"10.1172\/JCI4004","article-title":"Tumor immunity and autoimmunity induced by immunization with homologous DNA","volume":"102","author":"Weber","year":"1998","journal-title":"J. Clin. 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