Galectin inhibitory disaccharides promote tumour immunity in a breast cancer model.
High level galectin-1 expression results in cancer cell evasion of the immune response, increased tumour survival and aggressive metastases. Using a galectin-1 polyclonal antibody, high levels of galectin-1 protein were shown to be expressed by breast cancer cells established from FVB/N MMTV-c-neu mice as well as by the B16F10 melanoma cell line. In mixed lymphocyte cultures using tumour cells as antigenic stimulators, addition of recombinant galectin-1 dose-dependently inhibited lymphocyte production. Disaccharides were identified that inhibited galectin-1 function and increased growth and activation of CD8(+) CTL's killing cancer cells. X-ray crystallographic structures of human galectin-1 in complex with inhibitory disaccharides revealed their mode of binding. Combining galectin-blocking carbohydrates as adjuvants with vaccine immunotherapy in vivo to promote immune responses significantly decreased tumour progression and improved the outcomes for tumour challenged mice. This is the first report showing that suitably selected galectin-1 blocking disaccharides will act as adjuvants promoting vaccine stimulated immune responses against tumours in vivo.
Stannard
Kimberley A
KA
School of Medical Science, Griffith University, Southport, QLD 4222, Australia. k.stannard@griffith.edu.au
Collins
Patrick M
PM
Ito
Koichi
K
Sullivan
Emily M
EM
Scott
Stacy A
SA
Gabutero
Elwyn
E
Darren Grice
I
I
Low
Pauline
P
Nilsson
Ulf J
UJ
Leffler
Hakon
H
Blanchard
Helen
H
Ralph
Stephen J
SJ
D000818:Animals; D015153:Blotting, Western; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004187:Disaccharides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D037483:Galectin 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D037502:Galectin 3 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D037161:Galectins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007109:Immunity / Q000187:drug effects*; D007167:Immunotherapy / Q000379:methods; D008325:Mammary Neoplasms, Experimental / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D051379:Mice; D008815:Mice, Inbred Strains; D008958:Models, Molecular; D011485:Protein Binding; D013862:Thiogalactosides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D047368:Tumor Burden / Q000187:drug effects
D019496:Cancer Vaccines; D004187:Disaccharides; D037483:Galectin 1; D037502:Galectin 3; D037161:Galectins; D013862:Thiogalactosides; C005608:lactobionic acid