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Generation and utilization of polyfunctional anti-tumor CD4+ T cells
© Zhou and Ding 2015
Published: 4 November 2015
There is accumulating evidence that polyfunctional T cells, effector T cells capable of simultaneously producing multiple pro-inflammatory cytokines, are more efficacious in controlling infection and cancer. However, how polyfunctional CD4+ effector cells are induced is not mechanistically understood.
In this study we established that IL7 can promote the acquisition of polyfunctionality in naïve CD4+ T cells upon antigenic stimulation in vitro. In particular, IL7-conditioned polyfunctional CD4+ T cells can concomitantly express IFN-γ, TNF-α, IL-2 and granzyme B, with a separate IL4-producing population. We demonstrated that IL7 signaling resulted in increased histone acetylation in the promoters of effector molecules including IFN-γ, TNF-Αalpha, IL-2 and granzyme B, but not in Foxp3 and PD1, suggesting a selective enhancement in chromatin accessibility.
Mechanistically, STAT5 is required for IL7-driven polyfunctionality as expression of constitutive active STAT5 mutant in CD4+ T cells conferred polyfunctionality to CD4+ T cells even in the absence of IL7, whereas expression of dominant negative STAT5 mutant abolished IL7-driven polyfunctionality. Surprisingly, fully armed polyfunctional CD4+ T cells did not exhibit potent anti-tumor effect when adoptively transferred into mice with established B cell lymphoma, suggesting the dominance of immune suppression in the tumor microenvironment. Durable curative anti-tumor effect can be achieved by providing TriVax, a vaccine consisting of peptide, poly-IC adjuvant and OX40 antibody, following polyfunctional CD4+ T cell transfer.
Our results provide novel insights into the generation of polyfunctional CD4+ effector cells and their potential usage in cancer immunotherapy.
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.