TY - JOUR
T1 - Folate receptor-targeted immunotherapy
T2 - Induction of humoral and cellular immunity against hapten-decorated cancer cells
AU - Lu, Yingjuan
AU - Sega, Emanuela
AU - Low, Philip S.
PY - 2005/9/20
Y1 - 2005/9/20
N2 - We previously exploited the frequent overexpression of folate receptors on cancer cells to decorate malignant cell surfaces selectively with folate-hapten conjugates. In antihapten-immunized hosts, this targeted localization of foreign haptens to tumor cells led to rapid accumulation of autologous antihapten IgG, which in turn yielded potent antitumor activity upon stimulation with cytokines (IL-2, IFN-α). In an effort to understand the effector mechanisms responsible for tumor regression, we have now investigated the involvement of both humoral and cellular immune components in the tumor destruction process. We report that the dependence of therapeutic efficacy on folate-hapten concentration is bimodal, suggesting that the conjugate must bridge between a cell surface FR and an antihapten IgG in order to mediate killing. Studies with cancer cells in vitro further demonstrate that folate-fluorescein-marked tumor cells are killed primarily by antibody-dependent cellular cytotoxicity and phagocytosis, with no contribution from complement-dependent mechanisms. Investigations of specific immune cell involvement also reveal that asialo-GM1+-natural killer cells, macrophages, CD4+ T cells and CD8+ T cells contribute significantly to recognition/removal of the cancer mass, and that elimination of these cell types markedly compromises the therapy. Because the initial antibody-dependent stage of tumor cell killing is shown to lead to a long-term antibody-independent cellular immunity that involves both CD4+ and CD8+ T cells, we propose that Fc receptor-expressing immune cells not only initiate destruction of the IgG-marked tumor cells, but also participate in presentation of endogenous tumor antigens in a manner that leads to long-term cellular immunity.
AB - We previously exploited the frequent overexpression of folate receptors on cancer cells to decorate malignant cell surfaces selectively with folate-hapten conjugates. In antihapten-immunized hosts, this targeted localization of foreign haptens to tumor cells led to rapid accumulation of autologous antihapten IgG, which in turn yielded potent antitumor activity upon stimulation with cytokines (IL-2, IFN-α). In an effort to understand the effector mechanisms responsible for tumor regression, we have now investigated the involvement of both humoral and cellular immune components in the tumor destruction process. We report that the dependence of therapeutic efficacy on folate-hapten concentration is bimodal, suggesting that the conjugate must bridge between a cell surface FR and an antihapten IgG in order to mediate killing. Studies with cancer cells in vitro further demonstrate that folate-fluorescein-marked tumor cells are killed primarily by antibody-dependent cellular cytotoxicity and phagocytosis, with no contribution from complement-dependent mechanisms. Investigations of specific immune cell involvement also reveal that asialo-GM1+-natural killer cells, macrophages, CD4+ T cells and CD8+ T cells contribute significantly to recognition/removal of the cancer mass, and that elimination of these cell types markedly compromises the therapy. Because the initial antibody-dependent stage of tumor cell killing is shown to lead to a long-term antibody-independent cellular immunity that involves both CD4+ and CD8+ T cells, we propose that Fc receptor-expressing immune cells not only initiate destruction of the IgG-marked tumor cells, but also participate in presentation of endogenous tumor antigens in a manner that leads to long-term cellular immunity.
KW - Cytokine immunostimulation
KW - Fc-expressing immune cells
KW - Folate receptor
KW - Targeting of folate-hapten conjugates
KW - Tumor immunotherapy
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U2 - 10.1002/ijc.21126
DO - 10.1002/ijc.21126
M3 - Article
C2 - 15828051
AN - SCOPUS:23244454577
VL - 116
SP - 710
EP - 719
JO - International Journal of Cancer
JF - International Journal of Cancer
SN - 0020-7136
IS - 5
ER -