Transforming Growth Factor beta (TGF-β) is a pleiotropic cytokine produced in large amounts within cancer microenvironments that will ultimately promote neoplastic progression, notably by suppressing the host’s T-cell immunosurveillance. This effect is mostly due to the well-known inhibitory effect of TGF-β on T cell proliferation, activation, and effector functions. Moreover, TGF-β subverts T cell immunity by favoring regulatory T-cell differentiation, further reinforcing immunosuppression within tumor microenvironments. These findings stimulated the development of many strategies to block TGF-β or its signaling pathways, either as monotherapy or in combination with other therapies, to restore anti-cancer immunity. Paradoxically, recent studies provided evidence that TGF-β can also promote differentiation of certain inflammatory populations of T cells, such as Th17, Th9, and resident-memory T cells (Trm), which have been associated with improved tumor control in several models. Here, we review current advances in our understanding of the many roles of TGF-β in T cell biology in the context of tumor immunity and discuss the possibility to manipulate TGF-β signaling to improve cancer immunotherapy.

To stimulate a productive T cell response, dendritic cells (DC) must undergo maturation characterized by heightened cell surface expression of MHC and costimulatory molecules as well as cytokine production. Conversely, the inhibition of DC maturation is a central mechanism of immune tolerance. The control of the DC maturation process relies on the integration of several cellular stimulatory or inhibitory signals. The soluble factors and their receptors controlling this central aspect of DC biology are incompletely characterized. We show that murine bone marrow-derived DC (BMDC) maturation induced by LPS, as opposed to polyinosinic:polycytidylic acid or cytosine-phosphate-guanine, is robustly inhibited by vascular endothelial growth factor (VEGF), a previously identified immunosuppressive cytokine. Using BMDC from wild type and conditional knockout mice, we show that neuropilin-1 (NRP-1), a known receptor of VEGF, is necessary to suppress LPS-dependent BMDC maturation. The absence of NRP-1 had no ostensible effects on the biology of BMDC in the absence of VEGF. However, NRP-1-deficient BMDC remained completely insensitive to the VEGF-dependent inhibition of BMDC maturation in culture. In the presence of VEGF, NRP-1 directly interacted with the LPS receptor TLR4 and suppressed downstream signaling through ERK and NF-κβ, resulting in a sharp inhibition of MHC class II and costimulatory molecules (CD40, CD86) expression as well as proinflammatory cytokine production. Consequently, we identify NRP-1 as a target to optimize DC maturation within environments that are rich in VEGF, such as tumors.

The adoptive transfer of ex vivo--expanded T cells is a promising approach to treat several malignancies. Several lines of evidence support that the infusion of T cells with early memory features, capable of expanding and persisting after transfer, are associated with better outcomes. We report herein that exposure to exogenous TGFb during human T-cell stimulation ex vivo leads to the accumulation of early/central memory (Tcm) cells. Exposure to TGFb suppressed the expression of BLIMP-1, a key orchestrator of effector T-cell differentiation, and led to the upregulation of the memory-associated transcription factor ID3. Accordingly, this was associated with an early memory transcriptional signature in both CD4 þ and CD8 þ T-cell subsets. The T cells stimulated in the presence of TGFb expanded normally, and displayed polyfunctional features and no suppressive activity. The adoptive transfer of ex vivo--stimulated T cells into immunodeficient mice confirmed that TGFb-conditioned cells had an enhanced capacity to persist and mediate xenogeneic graft-versushost disease, as predicted by their early T-cell memory phenotype. Chimeric antigen receptor--expressing T cells generated in the presence of exogenous TGFb were cytotoxic and more effective at controlling tumor growth in immunodeficient animals. This work unveils a new role for TGFb in memory T-cell differentiation and indicates that TGFb signaling may be harnessed to program Tcm differentiation in the context of ex vivo T-cell stimulation for adoptive immunotherapy in humans.

Using a rapid, clinically compliant culture system, we show that autologous BK virus-specific T cell lines can be reliably generated from viremic KTR. Our results pave the way for the treatment or prevention of PVAN with adoptive immunotherapy.

Adoptive immunotherapy using ex vivo differentiated and expanded T cell lines can be remarkably efficient to treat cancer and infections. Unfortunately, the process of ex vivo T cell stimulation can lead to terminal effector differentiation and functional exhaustion thereby limiting the persistence and therapeutic effects of these T cells after transfer. Accumulating evidence suggests that, owing to their proliferative capacity, self-renewal ability and long term persistence in vivo, T cells bearing a central memory (CD45RO+/CD62L+ - Tcm) instead of an effector memory (CD45RO+/CD62L- - Tem) phenotype before adoptive transfer can mediate more significant therapeutic activity. Transforming-growth factor-beta (TGF-β) is a pleiotropic cytokine that influences several aspects of T-cell biology and that is best known for its growth suppression and immunosuppressive activity. We show that TGF-β signaling can have a profound impact on the number of CD4 and CD8 T cells expressing the Tcm and Tem phenotype after anti-CD3e and anti-CD28 stimulation without altering the number of cells recovered at the end of the culture and without inducing regulatory T cells. By enhancing the percentage of the lymph-node homing receptors, L-selectin (CD62L) and CC-chemokine receptor 7 (CCR7) expressing cells, exogenous TGF-β, added to the culture medium to a concentration of 5 ng/ml, favors Tcm over Tem cell accumulation at 7 days (CD4+: 55.80 vs 35.51% (P= 0.0074); CD8+: 56.9 vs 40.3% (P= 0.0063)). Reciprocally, the inhibition of TGF-β signaling with a TGF-β receptor kinase inhibitor (GW788388) accentuated Tem phenotype acquisition. Importantly, these effects of TGF-β on Tcm marker expression were maintained in the presence of exogenous cytokines commonly used in ex-vivo cultures for adoptive immunotherapy (IL-2, IL-7 and IL-15). The manipulation of TGF-β signaling did not increase the expression of exhaustion markers (KRLG-1, CD57) but exogenous TGF-β decreased interferon-gamma (IFN-γ) expression. No effect was noted on TNF-α and IL-2 expression as well as on the percentage of polyfunctional cells generated. We also found that modulating TGF-β signaling during the course of clinically relevant cultures capable of expanding T-cells specific for Epstein-Barr virus LMP2 protein antigens, in the presence of IL-7 and IL-15, could increase the number of CD4 Tcm cells, even 2 weeks after the withdrawal of TGF-β from the culture (38.24 vs 27.82, N=3) without compromising antigen-specific IFN-γ release. In conclusion, the modulation of TGF-β signaling can significantly alter Tcm and Tem phenotype acquisition and may therefore be used to optimize Tcm phenotype expression by ex-vivo pathogen/antigen-specific T cells expanded for adoptive immunotherapy. Disclosures No relevant conflicts of interest to declare.

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