Abstract
Genetic modification of whole-cell cancer vaccines to augment their efficacies has a history of over two and a half decades. Various genes and gene combinations, targeting different aspects of immune responses have been tested in pursuit of potent adjuvant effects. Here we show that co-expression of two cytokine members of the common cytokine receptor γ-chain family, IL-21 and IL-7, in whole-cell cancer vaccines boosts antitumor immunity in a CD4+ and CD8+ T cell-dependent fashion. It also generates effective immune memory. The vaccine-elicited short-term effects positively correlated with enhanced infiltration of CD4+ and CD8+ effector T cells, and the long-term effects positively correlated with enhanced infiltration of effector memory T cells, especially CD8+ effector memory T cells. Preliminary data suggested that the vaccine exhibited good safety profile in murine models. Taken together, the combination of IL-21 and IL-7 possesses potent adjuvant efficacy in whole-cell vaccines. This finding warrants future development of IL-21 and IL-7 co-expressing whole-cell cancer vaccines and their relevant combinatorial regimens.
Highlights
Vaccination with irradiated tumor cells that are genetically modified to express genes targeting different aspects of immune responses to promote antitumor immunity has been a focus in the field of tumor immunotherapeutics for decades[1,2,3]
We have shown that vaccination with tumor cells co-expressing IL-21 and IL-7 elicited potent antitumor responses in both prophylactic and therapeutic tumor models
CD4+ and CD8+ effector T cells, and the long-term effects positively correlated with enhanced infiltration of effector memory T cells, especially CD8+ Tems
Summary
Vaccination with irradiated tumor cells that are genetically modified to express genes targeting different aspects of immune responses to promote antitumor immunity has been a focus in the field of tumor immunotherapeutics for decades[1,2,3]. Various signals stimulate T cell to boost the potency of adaptive immune responses, a subset of which is conducted by common cytokine receptor γ-chain family cytokines, comprising IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21. Their receptors, sharing a common γsubunit, transduce signals through the Jak-STAT pathway among others, on binding to their respective ligands. IL-21 receptor, expressed on naïve, effector and memory T cells, albeit at varied levels, signals mainly through STAT3, which is a distinctive bias from other members of this receptor family. While IL-7 receptor, expressed on naïve and memory T cells, almost absent on effector T cells though, signals mainly through STAT54,5. The vaccine formulation were examined for safety concerns in murine models
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