Rapamycin delays growth of Wnt-1 tumors in spite of suppression of host immunity.
BACKGROUND
Rapamycin, an inhibitor of mammalian target of Rapamycin (mTOR), is an immunosuppressive agent that has anti-proliferative effects on some tumors. However, the role of Rapamycin-induced immune suppression on tumor progression has not been examined.


METHODS
We developed a transplantation model for generation of mammary tumors in syngeneic recipients that can be used to address the role of the immune system on tumor progression. We examined the effect of Rapamycin on the immune system and growth of MMTV-driven Wnt-1 mammary tumors which were transplanted into irradiated and bone marrow-reconstituted, or naïve mice.


RESULTS
Rapamycin induced severe immunosuppression and significantly delayed the growth of Wnt-1 tumors. T cell depletion in spleen and thymus and reduction in T cell cytokine secretion were evident within 7 days of therapy. By day 20, splenic but not thymic T cell counts, and cytokine secretion recovered. We determined whether adoptive T cell therapy enhances the anti-cancer effect using ex vivo generated Rapamycin-resistant T cells. However, T cell transfer during Rapamycin therapy did not improve the outcome relative to drug therapy alone. Thus, we could not confirm that suppression of T cell immunity contributes to tumor growth in this model. Consistent with suppression of the mTOR pathway, decreased 4E-BP1, p70 S6-kinase, and S6 protein phosphorylation correlated with a decrease in Wnt-1 tumor cell proliferation.


CONCLUSIONS
Rapamycin has a direct anti-tumor effect on Wnt-1 breast cancer in vivo that involves inhibition of the mTOR pathway at doses that also suppress host immune responses.
Svirshchevskaya
Elena V
EV
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Miklukho-Maklaya Street 16/10, Moscow 117997, Moscow, Russia. esvir@mail.ibch.ru
Mariotti
Jacopo
J
Wright
Mollie H
MH
Viskova
Natalia Y
NY
Telford
William
W
Fowler
Daniel H
DH
Varticovski
Lyuba
L
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D002453:Cell Cycle / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D016219:Immunotherapy, Adoptive / Q000379:methods; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D051379:Mice; D020123:Sirolimus / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D051155:Wnt1 Protein / Q000096:biosynthesis* / Q000235:genetics
D000903:Antibiotics, Antineoplastic; D051155:Wnt1 Protein; C495246:Wnt1 protein, mouse; D020123:Sirolimus