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CD4+ T cells elicit host immune responses to MHC class II-negative ovarian cancer through CCL5 secretion and CD40-mediated licensing of dendritic cells.

Publication ,  Journal Article
Nesbeth, YC; Martinez, DG; Toraya, S; Scarlett, UK; Cubillos-Ruiz, JR; Rutkowski, MR; Conejo-Garcia, JR
Published in: J Immunol
May 15, 2010

T cell adoptive transfer strategies that have produced clinical remissions against specific tumors have so far produced disappointing results against ovarian cancer. Recent evidence suggests that adoptively transferred CD4(+) T cells can trigger endogenous immune responses in particular patients with ovarian cancer through unknown mechanisms. However, conflicting reports suggest that ovarian cancer-infiltrating CD4(+) T cells are associated with negative outcomes. In this study, we elucidate the phenotypic attributes that enable polyclonal CD4(+) T cells briefly primed against tumor Ags to induce therapeutically relevant endogenous antitumor immune responses. Our results unveil a therapeutic mechanism whereby tumor-primed CD4(+) T cells transferred into ovarian cancer-bearing mice secrete high levels of CCL5, which recruits endogenous CCR5(+) dendritic cells to tumor locations and activate them through CD40-CD40L interactions. These newly matured dendritic cells are then able to prime tumor-specific endogenous CD8(+) T cells, which mediate long-term protection. Correspondingly, administration of tumor-primed CD4(+) T cells significantly delayed progression of MHC class II(-) ovarian cancers, similarly to CD8(+) T cells only, and directly activated wild-type but not CD40-deficient dendritic cells recruited to the tumor microenvironment. Our results unveil a CCL5- and CD40L-dependent mechanism of transferring immunity from exogenously activated CD4(+) T cells to tumor-exposed host cells, resulting in sustained antitumor effects. Our data provide a mechanistic rationale for incorporating tumor-reactive CD4(+) T cells in adoptive cell transfer immunotherapies against ovarian cancer and underscore the importance of optimizing immunotherapeutic strategies for the specific microenvironment of individual tumors.

Duke Scholars

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Published In

J Immunol

DOI

EISSN

1550-6606

Publication Date

May 15, 2010

Volume

184

Issue

10

Start / End Page

5654 / 5662

Location

United States

Related Subject Headings

  • Receptors, CCR5
  • Ovarian Neoplasms
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Mice
  • Immunotherapy, Adoptive
  • Immunology
  • Histocompatibility Antigens Class II
  • Female
  • Disease Models, Animal
 

Citation

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MLA
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Nesbeth, Y. C., Martinez, D. G., Toraya, S., Scarlett, U. K., Cubillos-Ruiz, J. R., Rutkowski, M. R., & Conejo-Garcia, J. R. (2010). CD4+ T cells elicit host immune responses to MHC class II-negative ovarian cancer through CCL5 secretion and CD40-mediated licensing of dendritic cells. J Immunol, 184(10), 5654–5662. https://doi.org/10.4049/jimmunol.0903247
Nesbeth, Yolanda C., Diana G. Martinez, Seiko Toraya, Uciane K. Scarlett, Juan R. Cubillos-Ruiz, Melanie R. Rutkowski, and Jose R. Conejo-Garcia. “CD4+ T cells elicit host immune responses to MHC class II-negative ovarian cancer through CCL5 secretion and CD40-mediated licensing of dendritic cells.J Immunol 184, no. 10 (May 15, 2010): 5654–62. https://doi.org/10.4049/jimmunol.0903247.
Nesbeth YC, Martinez DG, Toraya S, Scarlett UK, Cubillos-Ruiz JR, Rutkowski MR, et al. CD4+ T cells elicit host immune responses to MHC class II-negative ovarian cancer through CCL5 secretion and CD40-mediated licensing of dendritic cells. J Immunol. 2010 May 15;184(10):5654–62.
Nesbeth, Yolanda C., et al. “CD4+ T cells elicit host immune responses to MHC class II-negative ovarian cancer through CCL5 secretion and CD40-mediated licensing of dendritic cells.J Immunol, vol. 184, no. 10, May 2010, pp. 5654–62. Pubmed, doi:10.4049/jimmunol.0903247.
Nesbeth YC, Martinez DG, Toraya S, Scarlett UK, Cubillos-Ruiz JR, Rutkowski MR, Conejo-Garcia JR. CD4+ T cells elicit host immune responses to MHC class II-negative ovarian cancer through CCL5 secretion and CD40-mediated licensing of dendritic cells. J Immunol. 2010 May 15;184(10):5654–5662.

Published In

J Immunol

DOI

EISSN

1550-6606

Publication Date

May 15, 2010

Volume

184

Issue

10

Start / End Page

5654 / 5662

Location

United States

Related Subject Headings

  • Receptors, CCR5
  • Ovarian Neoplasms
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Mice
  • Immunotherapy, Adoptive
  • Immunology
  • Histocompatibility Antigens Class II
  • Female
  • Disease Models, Animal