Targeting the lymphotoxin-beta receptor with agonist antibodies as a potential cancer therapy
The lymphotoxin-beta receptor (LT beta R) is a tumor necrosis factor receptor family member critical for the development and maintenance of various lymphoid microenvironments. Herein, we show that agonistic anti-LT beta R monoclonal antibody (mAb) CBE11 inhibited tumor growth in xenograft models and potentiated tumor responses to chemotherapeutic agents. In a syngeneic colon carcinoma tumor model, treatment of the tumor-bearing mice with an agonistic antibody against murine LT beta R caused increased lymphocyte infiltration and necrosis of the tumor. A pattern of differential gene expression predictive of cellular and xenograft response to LT beta R activation was identified in a panel of colon carcinoma cell lines and when applied to a panel of clinical colorectal tumor samples indicated 35% likelihood a tumor response to CBE11. Consistent with this estimate, CBE11 decreased tumor size and/or improved long-term animal survival with two of six independent orthotopic xenografts prepared from surgical colorectal carcinoma samples. Targeting of LT beta R with agonistic mAbs offers a novel approach to the treatment of colorectal and potentially other types of cancers.
|Authors||Lukashev, M.;LePage, D.;Wilson, C.;Bailly, V.;Garber, E.;Lukashin, A.;Ngam-ek, A.;Zeng, W.;Allaire, N.;Perrin, S.;Xu, X.;Szeliga, K.;Wortham, K.;Kelly, R.;Bottiglio, C.;Ding, J.;Griffith, L.;Heaney, G.;Silverio, E.;Yang, W.;Jarpe, M.;Fawell, S.;Reff, M.;Carmillo, A.;Miatkowski, K.;Amatucci, J.;Crowell, T.;Prentice, H.;Meier, W.;Violette, S. M.;Mackay, F.;Yang, D.;Hoffman, R.;Browning, J. L. :|
|Publisher Name||CANCER RESEARCH|
|URL link to publisher's version||http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17018619|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/2084|