title: Robust anti-tumor immunity and memory in Rag-1-deficient mice following adoptive transfer of cytokine-primed splenocytes and tumor CD80 expression.
abstract: Successful immunotherapy of solid tumors has proven difficult to achieve. The aim of the current study was to further investigate the effects of peripheral CD80-mediated co-stimulation on the efficacy of polyclonal anti-tumor effector CTL in an adoptive transfer model. Splenocytes obtained from wild-type mice immunized with CD80-transduced EL4 tumor cells were expanded in vitro in the presence of either IL-12 or IL-15 and irradiated CD80-transduced EL4 tumor cells. Polyclonal CD8 T cells were the major subset in the effector population. Primed effector cells were adoptively transferred into immuno-deficient Rag-1-deficient mice which were then challenged with syngeneic vector-control or CD80-transduced EL4 tumor cells. Expression of CD80 enhanced the elimination of EL4 tumors and mouse survival. Both IL-12 and IL-15 cultured cells had enhanced cytotoxicity. Importantly, anti-tumor memory was maintained without tumor evasion following re-challenge with either CD80-transduced and vector-control EL4 cells. We also show, using antibody-mediated depletion, that endogenous NK cells present in Rag-1-deficient mice exert anti-EL4 tumor activity that is enhanced by CD80 expression. Collectively these data show that peripheral co-stimulation by tumor expression of CD80 results in enhanced anti-tumor efficacy of NK and polyclonal effector T cells, and suggest that TCR repertoire diversity helps protect against tumor escape and provides memory with resultant robust immunity to subsequent tumor challenge irrespective of CD80 status.
authors.affiliation: Gene Therapy Research Unit, The Children's Hospital at Westmead and Children's Medical Research Institute, Westmead, NSW, Australia.
authors.forename: Priyadarshini L
authors.initials: PL
authors.lastname: Ganesan
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Alexander
authors.forename: Debbie
authors.initials: D
authors.lastname: Watson
authors.forename: Grant J
authors.initials: GJ
authors.lastname: Logan
authors.forename: Geoff Y
authors.initials: GY
authors.lastname: Zhang
authors.forename: Ian E
authors.initials: IE
authors.lastname: Alexander
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry*; D018122:B7-1 Antigen / Q000096:biosynthesis*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism*; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000235:genetics* / Q000502:physiology*; D018664:Interleukin-12 / Q000096:biosynthesis; D019409:Interleukin-15 / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D013154:Spleen / Q000166:cytology*; D013601:T-Lymphocytes / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D018122:B7-1 Antigen; D016207:Cytokines; D018398:Homeodomain Proteins; D019409:Interleukin-15; C064658:RAG-1 protein; D018664:Interleukin-12