Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-34641
Haynes, N M; Hawkins, E D; Li, M; McLaughlin, N M; Hämmerling, G J; Schwendener, R; Winoto, A; Wensky, A; Yagita, H; Takeda, K; Kershaw, M H; Darcy, P K; Smyth, M J (2010). CD11c(+) dendritic cells and B cells contribute to the tumoricidal activity of anti-DR5 antibody therapy in established tumors. Journal of Immunology, 185(1):532-541.
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The selective targeting of the tumor-associated death-inducing receptors DR4 and DR5 with agonistic mAbs has demonstrated preclinical and clinical antitumor activity. However, the cellular and molecular mechanisms contributing to this efficacy remain poorly understood. In this study, using the first described C57BL/6 (B6) TRAIL-sensitive experimental tumor models, we have characterized the innate and adaptive immune components involved in the primary rejection phase of an anti-mouse DR5 (mDR5) mAb, MD5-1 in established MC38 colon adenocarcinomas. FcR mediated cross-linking of MD5-1 significantly inhibited the growth of MC38 colon adenocarcinomas through the induction of TRAIL-R-dependent tumor cell apoptosis. The loss of host DR5, TRAIL, perforin, FasL, or TNF did not compromise anti-DR5 therapy in vivo. By contrast, anti-DR5 therapy was completely abrogated in mice deficient of B cells or CD11c(+) dendritic cells (DCs), providing the first direct evidence that these cells play a critical role. Importantly, the requirement for an intact B cell compartment for optimal anti-DR5 antitumor efficacy was also observed in established AT-3 mammary tumors. Interestingly, MD5-1-mediated apoptosis as measured by early TUNEL activity was completely lost in B cell-deficient muMT mice, but intact in mice deficient in CD11c(+) DCs. Overall, these data show that Ab-mediated targeting of DR5 triggers tumor cell apoptosis in established tumors in a B cell-dependent manner and that CD11c(+) DCs make a critical downstream contribution to anti-DR5 antitumor activity.
|Item Type:||Journal Article, refereed, original work|
|Communities & Collections:||04 Faculty of Medicine > Institute of Molecular Cancer Research|
07 Faculty of Science > Institute of Molecular Cancer Research
|DDC:||570 Life sciences; biology|
|Date:||01 July 2010|
|Deposited On:||06 Jul 2010 14:49|
|Last Modified:||08 Dec 2012 09:40|
|Publisher:||American Association of Immunologists|
|Free access at:||Publisher DOI. An embargo period may apply.|
|WoS Citation Count:||11|
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