Cn. Baxevanis et al., Tumor-specific CD4(+) T lymphocytes from cancer patients are required for optimal induction of cytotoxic T cells against the autologous tumor, J IMMUNOL, 164(7), 2000, pp. 3902-3912
This study focuses on the specific CD4(+) T cell requirement for optimal in
duction of cytotoxicity against MHC class II negative autologous tumors (Au
Tu) collected from patients with various types of cancer at advanced stages
. CD4(+) T cells were induced in cultures of cancer patients' malignant eff
usion-associated mononuclear cells with irradiated AuTu (mixed lymphocyte t
umor cultures (MLTC)) in the presence of recombinant IL-2 and recombinant I
L-7, Tumor-specific CD4(+) T cells did not directly recognize the AuTu cell
s, but there was an MHC class II-restricted cross-priming by autologous den
dritic cells (DCs), used as APC, CD8(+) CTL, also induced during the MLTC,
lysed specifically AuTu cells or DCs pulsed with AuTu peptide extracts (aci
d 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 auto
logous CD4(+) T cells were able, in the absence of CD4(+) T cells, to stimu
late CD8(+) T cells to lyse autologous tumor targets. Such activated CD8(+)
T cells produced IL-2, IFN-gamma, TNF-alpha, and GM-CSP, The process of th
e activation of AWE-pulsed DCs by CD4(+) T cells could be inhibited with an
ti-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 fi
rst time in patients with metastatic cancer the essential role of CD4+ Th c
ell-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 i
nducing T cell help in vivo.