Abstract
Increased availability of homeostatic cytokines is considered a major mechanism by which lymphodepletion enhances the efficacy of adoptive T cell therapy (ACT). IL-7 is one such cytokine capable of augmenting the function of tumor-reactive CD8+ T cells. However, whether host-derived IL-7 plays a role in driving the proper function of CD4+ T cells in an ACT setting remains unclear. Here we report that lymphodepleting chemotherapy by cyclophosphamide (CTX) does not lead to increased availability of the endogenous IL-7 in mice. Despite of a paucity of IL-7 in the immune milieu, CTX preconditioning allowed adoptively transferred naïve tumor-specific CD4+ T cells to undergo effector differentiation and regain IL-7Rα expression, giving rise to IL-7-responsive polyfunctional CD4+ effector cells. Correspondingly, supplementation of exogenous recombinant IL-7 markedly amplified and sustained polyfunctional CD4+ effector cells, resulting in improved therapeutic outcome in a mouse lymphoma model. We further demonstrated that the immune-enhancing effects of IL-7 were also applicable to donor CD4+ T cells pre-activated under Th1 polarizing condition. These findings suggest caution in relying on the endogenous IL-7 to enhance donor T cell expansion and persistence after lymphodepleting chemotherapy, and highlight the usefulness of recombinant IL-7 as an adjuvant for adoptive immunotherapy.
Highlights
IL-7 is a hematopoietic growth factor involved in regulating multiple aspects of T cell biology including survival, homeostasis, metabolism and memory[1,2]
We and others previously reported that host preconditioning with CTX or total body irradiation (TBI) allows adoptively transferred tumor-specific CD4+ T cells to differentiate into polyfunctional effector cells characterized by their ability to concomitantly express multiple effector molecules including CD40L, IFNγ, IL-2, TNFα and granzyme B11,25–27
The results indicate that CTX preconditioning is a prerequisite for donor CD4+ T cells to acquire IL-7 responsiveness, which correlates with the functional status of tumor-reactive CD4+ T cells
Summary
IL-7 is a hematopoietic growth factor involved in regulating multiple aspects of T cell biology including survival, homeostasis, metabolism and memory[1,2]. CD4+ T cells can act as effector cells to execute direct tumor lysis through granzyme B11,12. CD4+ T cells can potentiate the activation of other tumor-reactive immune cells via CD40L expression and by release of www.nature.com/scientificreports/. We and others previously reported that host preconditioning with CTX or TBI allows adoptively transferred tumor-specific CD4+ T cells to differentiate into polyfunctional effector cells characterized by their ability to concomitantly express multiple effector molecules including CD40L, IFNγ, IL-2, TNFα and granzyme B11,25–27. We seek to investigate if induction of polyfunctional CD4+ T cells relies on increased IL-7 availability resulted from lymphodepleting preparative chemotherapy. We report the surprising finding that CTX-based lymphodepleting chemotherapy does not lead to a measurable increase in IL-7 availability. We show that supplementation of exogenous IL-7 promotes the expansion and maintenance of in vivo-differentiated polyfunctional CD4+ effector cells or in vitro-generated Th1 cells, supporting the use of IL-7 as an adjuvant for adoptive immunotherapy
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