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Combination immunotherapy of B16 melanoma using anti-cytotoxic T lymphocyte-associated 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.

van Elsas A, Hurwitz AA, Allison JP - J. Exp. Med. (1999)

Bottom Line: We examined the effectiveness of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade, alone or in combination with a granulocyte/macrophage colony-stimulating factor (GM-CSF)-expressing tumor cell vaccine, on rejection of the highly tumorigenic, poorly immunogenic murine melanoma B16-BL6.The same treatment regimen was found to be therapeutically effective against outgrowth of preestablished B16-F10 lung metastases, inducing long-term survival.Depigmentation was found to occur in CD4-depleted mice, strongly suggesting that the effect was mediated by CTLs.

View Article: PubMed Central - PubMed

Affiliation: Howard Hughes Medical Institute, Cancer Research Laboratory, Department of Molecular and Cellular Biology, University of California, Berkeley 94720-3200, USA.

ABSTRACT
We examined the effectiveness of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade, alone or in combination with a granulocyte/macrophage colony-stimulating factor (GM-CSF)-expressing 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.

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Rejection of B16-BL6 or B16-F10 as a result of treatment with anti–CTLA-4 and GM-CSF–producing vaccines causes autoimmune skin and hair depigmentation. After successful treatment for B16-BL6 subcutaneously or B16-F10 intravenously, C57Bl/6 mice developed skin and hair depigmentation. (A) Depigmentation of both sites of vaccination and challenge, after rejection of a day 0 tumor. (B) Progressive depigmentation found in a mouse rejecting a B16-BL6 subcutaneous tumor, established 8 d before treatment started. (C) Depigmentation at the site of vaccination of a mouse cured from preestablished B16-F10 lung metastases.
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Figure 6: Rejection of B16-BL6 or B16-F10 as a result of treatment with anti–CTLA-4 and GM-CSF–producing vaccines causes autoimmune skin and hair depigmentation. After successful treatment for B16-BL6 subcutaneously or B16-F10 intravenously, C57Bl/6 mice developed skin and hair depigmentation. (A) Depigmentation of both sites of vaccination and challenge, after rejection of a day 0 tumor. (B) Progressive depigmentation found in a mouse rejecting a B16-BL6 subcutaneous tumor, established 8 d before treatment started. (C) Depigmentation at the site of vaccination of a mouse cured from preestablished B16-F10 lung metastases.

Mentions: Within 4–8 wk after challenge, 56% (38/68 cured mice) of the surviving mice developed depigmentation, starting at the sites of vaccination (left flank) and challenge (back) (Fig. 6 A). Moreover, depigmentation was observed at the site of vaccination in a similar proportion of mice surviving B16-F10 lung metastases (Fig. 6 B). Rejection of a B16-BL6 tumor established 8 d before start of treatment (Fig. 1) induced fast and progressive depigmentation appearing within 25 d after challenge and spreading to distant sites, indicating that a relatively strong antitumor response resulted in rapid manifestation of progressive depigmentation (Fig. 6 C). Depigmentation did occur in mice that received combination treatment in a prophylactic setting but at reduced frequency (not shown). Interestingly, depigmentation was not dependent on the presence of CD4+ T cells, as four of eight CD4-depleted mice rejecting their tumors also developed progressive depigmentation (Table ). In some cases, tumor-bearing mice (moribund despite treatment with anti–CTLA-4 and BL6/GM) were found to develop small areas of hair depigmentation at the site of progressive tumor growth. Depigmentation was never observed in the mice that were treated by BL6/GM-CSF vaccination without CTLA-4 blockade or in any of the other treatment groups. These findings suggest that CTLA-4 blockade allows for the activation of autoreactive lymphoid cells that are involved in rejection of a tumor derived from the melanocytic lineage and may also mediate rejection of normal pigment-containing cells in the skin and hair follicles expressing pigmentation antigens.


Combination immunotherapy of B16 melanoma using anti-cytotoxic T lymphocyte-associated 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.

van Elsas A, Hurwitz AA, Allison JP - J. Exp. Med. (1999)

Rejection of B16-BL6 or B16-F10 as a result of treatment with anti–CTLA-4 and GM-CSF–producing vaccines causes autoimmune skin and hair depigmentation. After successful treatment for B16-BL6 subcutaneously or B16-F10 intravenously, C57Bl/6 mice developed skin and hair depigmentation. (A) Depigmentation of both sites of vaccination and challenge, after rejection of a day 0 tumor. (B) Progressive depigmentation found in a mouse rejecting a B16-BL6 subcutaneous tumor, established 8 d before treatment started. (C) Depigmentation at the site of vaccination of a mouse cured from preestablished B16-F10 lung metastases.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2195583&req=5

Figure 6: Rejection of B16-BL6 or B16-F10 as a result of treatment with anti–CTLA-4 and GM-CSF–producing vaccines causes autoimmune skin and hair depigmentation. After successful treatment for B16-BL6 subcutaneously or B16-F10 intravenously, C57Bl/6 mice developed skin and hair depigmentation. (A) Depigmentation of both sites of vaccination and challenge, after rejection of a day 0 tumor. (B) Progressive depigmentation found in a mouse rejecting a B16-BL6 subcutaneous tumor, established 8 d before treatment started. (C) Depigmentation at the site of vaccination of a mouse cured from preestablished B16-F10 lung metastases.
Mentions: Within 4–8 wk after challenge, 56% (38/68 cured mice) of the surviving mice developed depigmentation, starting at the sites of vaccination (left flank) and challenge (back) (Fig. 6 A). Moreover, depigmentation was observed at the site of vaccination in a similar proportion of mice surviving B16-F10 lung metastases (Fig. 6 B). Rejection of a B16-BL6 tumor established 8 d before start of treatment (Fig. 1) induced fast and progressive depigmentation appearing within 25 d after challenge and spreading to distant sites, indicating that a relatively strong antitumor response resulted in rapid manifestation of progressive depigmentation (Fig. 6 C). Depigmentation did occur in mice that received combination treatment in a prophylactic setting but at reduced frequency (not shown). Interestingly, depigmentation was not dependent on the presence of CD4+ T cells, as four of eight CD4-depleted mice rejecting their tumors also developed progressive depigmentation (Table ). In some cases, tumor-bearing mice (moribund despite treatment with anti–CTLA-4 and BL6/GM) were found to develop small areas of hair depigmentation at the site of progressive tumor growth. Depigmentation was never observed in the mice that were treated by BL6/GM-CSF vaccination without CTLA-4 blockade or in any of the other treatment groups. These findings suggest that CTLA-4 blockade allows for the activation of autoreactive lymphoid cells that are involved in rejection of a tumor derived from the melanocytic lineage and may also mediate rejection of normal pigment-containing cells in the skin and hair follicles expressing pigmentation antigens.

Bottom Line: We examined the effectiveness of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade, alone or in combination with a granulocyte/macrophage colony-stimulating factor (GM-CSF)-expressing tumor cell vaccine, on rejection of the highly tumorigenic, poorly immunogenic murine melanoma B16-BL6.The same treatment regimen was found to be therapeutically effective against outgrowth of preestablished B16-F10 lung metastases, inducing long-term survival.Depigmentation was found to occur in CD4-depleted mice, strongly suggesting that the effect was mediated by CTLs.

View Article: PubMed Central - PubMed

Affiliation: Howard Hughes Medical Institute, Cancer Research Laboratory, Department of Molecular and Cellular Biology, University of California, Berkeley 94720-3200, USA.

ABSTRACT
We examined the effectiveness of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade, alone or in combination with a granulocyte/macrophage colony-stimulating factor (GM-CSF)-expressing 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.

Show MeSH
Related in: MedlinePlus