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

Overview

abstract

  • 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.

publication date

  • April 16, 2010

Research

keywords

  • CD4-Positive T-Lymphocytes
  • CD40 Antigens
  • Chemokine CCL5
  • Dendritic Cells
  • Histocompatibility Antigens Class II
  • Immunotherapy, Adoptive
  • Ovarian Neoplasms

Identity

PubMed Central ID

  • PMC2874073

Scopus Document Identifier

  • 77954723327

Digital Object Identifier (DOI)

  • 10.4049/jimmunol.0903247

PubMed ID

  • 20400704

Additional Document Info

volume

  • 184

issue

  • 10