In Vitro Priming of Adoptively Transferred T Cells with a RORγ Agonist Confers Durable Memory and Stemness In Vivo

Abstract

Adoptive T-cell transfer therapy is an FDA-approved treatment for leukemia that relies on the ex vivo expansion and reinfusion of a patient’s immune cells, which can be engineered with a chimeric antigen receptor (CAR) for more efficient tumor recognition. Type 17 T cells, controlled transcriptionally by RORγ, have been reported to mediate potent antitumor effects superior to those observed with conventionally expanded T cells. Here, we demonstrate that addition of a synthetic, small-molecule RORγ agonist during ex vivo expansion potentiates the antitumor activity of human Th17 and Tc17 cells redirected with a CAR. Likewise, ex vivo use of this agonist bolstered the antitumor properties of murine tumor-specific CD4+ and CD8+ T cells. Expansion in the presence of the RORγ agonist enhanced IL17A production without compromising IFNγ secretion in vitro. In vivo, cytokine neutralization studies revealed that IFNγ and IL17A were required to regress murine melanoma tumors. The enhanced antitumor effect of RORγ agonist treatment was associated with recovery of more donor T cells in the tumor and spleen; these cells produced elevated levels of cytokines months after infusion and expressed markers of long-lived stem and central memory cells such as Tcf7 and CD62L. Conversely, untreated cells mainly exhibited effector phenotypes in the tumor. Cured mice previously treated with agonist-primed T cells were protected from tumor rechallenge. Collectively, our work reveals that in vitro treatment with a RORγ agonist generates potent antitumor Type 17 effector cells that persist as long-lived memory cells in vivo. Significance: RORγ agonists can be used in vitro during T-cell expansion to enhance the efficacy of adoptive cell therapy (e.g., CAR-T) and to provide long-term protection against tumors.

Targeting Histone Deacetylase 6 Reprograms Interleukin‐17‐Producing Helper T Cell Pathogenicity and Facilitates Immunotherapies for Hepatocellular Carcinoma

“…Our data demonstrated that HDAC6‐depleted T H 17 cells activated IFN‐γ and granzyme B signaling in the HCC microenvironment and improved survival rate. This phenotype greatly supported a recent study which demonstrated that RoRγt agonist could potentiate adoptively transferred T‐cell therapy . Furthermore, because IFN‐γ could augment PD‐L1 to weaken tumor immune surveillance and a clinical case suggests that IL‐17A potentiates the effect of immune checkpoint therapy, we found the combination treatment by targeting HDAC6 and PD‐1 antagonist effectively eliminated advanced HCC, which partially relied on IL‐17A.…”

Dihydroartemisinin inhibits melanoma by regulating CTL/Treg anti-tumor immunity and STAT3-mediated apoptosis via IL-10 dependent manner

“…Alternatively, Th17 cells could be transformed into Treg cells, which exert immunosuppressive effects and weaken anti-tumor immunity [46]. Paradoxically, some studies have found that Th17 cells act as tumor suppressors [47,48]. In the current study, DHA treatment significantly decreased the expression of ROR-gt and phosphorylation of STAT3 ( Fig.…”

RORγ Structural Plasticity and Druggability

“…Overexpression of RORγ and RORγt can lead to obesity-associated insulin resistance and multiple autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, Crohn's disease and psoriasis. On the other hand, high RORγt activity can sometimes be beneficial and has been shown to enhance antitumor immunity by increasing IL-17, GM-CSF (granulocyte-macrophage colony-stimulating factor) secretion and decreasing PD-1 expression [4,5]. The pathological functions and the therapeutic potential of RORγ make it an intriguing drug target.…”