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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Nesbeth, YC; Martinez, DG; Toraya, S; Scarlett, UK; Cubillos-Ruiz, JR; Rutkowski, MR; Conejo-Garcia, JR

Published Date

  • May 15, 2010

Published In

Volume / Issue

  • 184 / 10

Start / End Page

  • 5654 - 5662

PubMed ID

  • 20400704

Pubmed Central ID

  • PMC2874073

Electronic International Standard Serial Number (EISSN)

  • 1550-6606

Digital Object Identifier (DOI)

  • 10.4049/jimmunol.0903247


  • eng

Conference Location

  • United States