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Blood, 1 July 2002, Vol. 100, No. 1, pp. 200-207
NEOPLASIA
Transgenic expression of CD40 ligand produces an in vivo
antitumor immune response against both CD40+ and
CD40 plasmacytoma cells
Gianpietro Dotti,
Barbara Savoldo,
Patricia Yotnda,
Donna Rill, and
Malcolm K. Brenner
From the Center for Cell and Gene Therapy, Baylor
College of Medicine, Houston, TX.
Because tumor-specific antigens have been identified in multiple
myeloma (MM), immunotherapy might provide an additional treatment modality for the disease. Expression of CD40 ligand (CD40L) proximate to the MM cells might serve this purpose, either by increasing their
capacity to present self-antigens by activation through their CD40
receptor or by the recruitment of professional antigen-presenting cells
(APCs) able to take up and present tumor-associated antigens. To
distinguish between these possibilities and predict whether human
CD40 myeloma might respond to this approach, we
examined 3 murine plasmacytoma cell lines, 2 (MPC-11 and S107)
expressing the CD40 molecule and 1 (X-24) lacking such expression.
Syngeneic BALB/CBYJ mice were inoculated subcutaneously with tumor
cells mixed with CL7.1 fibroblasts, retrovirally transduced to express
either the mCD40L or the neo gene. For all 3 plasmacytoma cell lines, coinjection with CL7.1/mCD40L significantly
reduced local tumor growth compared with controls. This effect was
mediated by a systemic antitumor immune response, since mice immunized
with tumor and CL7.1/mCD40L were resistant to subsequent challenge with
tumor, and tumor growth inhibition was abolished when CD8+
or CD4+ lymphocytes were depleted. Because expression of
CD40L gave equivalent protection from CD40+ and
CD40 tumors and transgenic-CD40L failed to up-regulate
costimulatory molecules in either tumor, the protective effects of
CD40L probably resulted from recruitment/activation of professional
APCs rather than from CD40 activation of plasmacytoma cells. As further
support of this concept, we found that mice were also well protected
if CL7.1 and CD40L were injected together with apoptotic
plasmacytoma cells from these tumors. Hence, transgenic CD40L
expression may produce an antimyeloma immune response against either
CD40+ or CD40 tumors and may be of
therapeutic value for both types of myeloma in humans.
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