Robust anti-tumor immunity and memory in Rag-1-deficient mice following adoptive transfer of cytokine-primed splenocytes and tumor CD80 expression.
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.
Ganesan
Priyadarshini L
PL
Gene Therapy Research Unit, The Children's Hospital at Westmead and Children's Medical Research Institute, Westmead, NSW, Australia.
Alexander
Stephen I
SI
Watson
Debbie
D
Logan
Grant J
GJ
Zhang
Geoff Y
GY
Alexander
Ian E
IE
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
D000970:Antineoplastic Agents; D018122:B7-1 Antigen; D016207:Cytokines; D018398:Homeodomain Proteins; D019409:Interleukin-15; C064658:RAG-1 protein; D018664:Interleukin-12