Robust anti-tumor immunity and memory in Rag-1-deficient mice following adoptive transfer of cytokine-primed splenocytes and tumor CD80 expression |
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Authors: | Priyadarshini L Ganesan Stephen I Alexander Debbie Watson Grant J Logan Geoff Y Zhang Ian E Alexander |
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Institution: | (1) Gene Therapy Research Unit, The Children’s Hospital at Westmead and Children’s Medical Research Institute, Westmead, NSW, Australia;(2) The Centre for Kidney Research, The Children’s Hospital at Westmead, Westmead, NSW, Australia;(3) The University of Sydney Discipline of Paediatrics and Child Health, Locked Bag 4001, Westmead, NSW, 2145, Australia;(4) Gene Therapy Research Unit, The Children’s Hospital at Westmead, Locked Bag 4001, Westmead, NSW, 2145, Australia |
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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-deficent 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. |
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Keywords: | Effector CTL Tumor-associated CD80 Cytokines NK cells |
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