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Cancer Immunology and Immunotherapy Center, Saint Savas Cancer Hospital, Athens, Greece
This study focuses on the specific CD4+ T cell
requirement for optimal induction of cytotoxicity against MHC class II
negative autologous tumors (AuTu) collected from patients with various
types of cancer at advanced stages. CD4+ T cells were
induced in cultures of cancer patients’ malignant effusion-associated
mononuclear cells with irradiated AuTu (mixed lymphocyte tumor cultures
(MLTC)) in the presence of recombinant IL-2 and recombinant IL-7.
Tumor-specific CD4+ T cells did not directly recognize the
AuTu cells, but there was an MHC class II-restricted cross-priming by
autologous dendritic cells (DCs), used as APC. CD8+ CTL,
also induced during the MLTC, lysed specifically AuTu cells or DCs
pulsed with AuTu peptide extracts (acid wash extracts (AWE)) in an MHC
class I-restricted manner. Removal of CD4+ T cells or DCs
from the MLTC drastically reduced the CD8+ CTL-mediated
cytotoxic response against the AuTu. AWE-pulsed DCs preincubated with
autologous CD4+ T cells were able, in the absence of
CD4+ T cells, to stimulate CD8+ T cells to lyse
autologous tumor targets. Such activated CD8+ T cells
produced IL-2, IFN-
, TNF-
, and GM-CSF. The process of the
activation of AWE-pulsed DCs by CD4+ T cells could be
inhibited with anti-CD40 ligand mAb. Moreover, the role of
CD4+ T cells in activating AWE-pulsed DCs was undertaken by
anti-CD40 mAb. Our data demonstrate for the first time in patients
with metastatic cancer the essential role of CD4+ Th
cell-activated DCs for optimal CD8+ T cell-mediated killing
of autologous tumors and provide the basis for the design of novel
protocols in cellular adoptive immunotherapy of cancer, utilizing
synthetic peptides capable of inducing T cell help in
vivo.
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