Abstract
IL-21 is known to promote anti-tumour immunity due to its ability to promote T cell responses and counteract Treg-mediated suppression. It has also been shown to limit Treg frequencies during tumour-antigen stimulations. However, whether this represents inhibition of FOXP3 induction in naïve CD4 T cells or curtailed expansion of natural Treg remains unclear. Moreover, whether this effect is maintained in an environment of tumour-derived immunosuppressive factors is not known. Here, we show that in the context of a number of cancers, naïve CD45RA+ CD4 T cells are induced to express high levels of FOXP3, and that FOXP3 expression correlates with inhibition of T cell proliferation. FOXP3 expression was most potently induced by tumours secreting higher levels of total and active TGFβ1 and this induction could be potently counteracted with IL-21, restoring T cell proliferation. We conclude that Treg induction in naïve T cells is a common phenomenon amongst a number of different cancers and that the ability of IL-21 to counteract this effect is further evidence of its promise in cancer therapy.
Highlights
Immunosuppressive FOXP3+ regulatory T cells (Treg) are known to accumulate within the tumour microenvironment in a variety of cancers and are associated with deficiencies in effector T cell responses and poorer outcomes [1]
To determine whether cancer cells are capable of directly inducing FOXP3 expression in naïve T cells, we purified CD45RA+ CD4 T cells from human peripheral blood and stimulated them for 5 days with anti-CD3/28 antibodycoated beads, in the presence or absence of culture supernatants from five cancer cell lines representing tumours of the colon, lung, liver and brain
FOXP3 induction was titratable, in that increasing the dose of cancer supernatant from 12.5 to 25%, and again to 50% of the total culture media leads to greater increases in FOXP3 expression in the naïve T cells, for supernatants representing colon cancers (Fig. 1c)
Summary
Immunosuppressive FOXP3+ regulatory T cells (Treg) are known to accumulate within the tumour microenvironment in a variety of cancers and are associated with deficiencies in effector T cell responses and poorer outcomes [1]. Represent a barrier to effective natural anti-tumour immunity, but whether intra-tumoural Treg are recruited from existing peripheral populations or are induced to differentiate from naive CD4 T cells within the tumour microenvironment remains unclear. Both mechanisms likely play an important role and interestingly, both in vitro and in vivo CD4 T cell stimulations with tumour antigens have been shown to induce Treg differentiation, even in the absence of other tumour-derived immunosuppressive factors [10, 11]. This has important implications within the tumour microenvironment, and for anti-tumour immunotherapeutic strategies, such
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