IL6 Induces an IL22+ CD8+ T-cell Subset with Potent Antitumor Function

Abstract

CD8 þ T cells can be polarized into several different subsets as defined by the cytokines they produce and the transcription factors that govern their differentiation. Here, we identified the polarizing conditions to induce an IL22-producing CD8 þ Tc22 subset, which is dependent on IL6 and the aryl hydrocarbon receptor transcription factor. Further characterization showed that this subset was highly cytolytic and expressed a distinct cytokine profile and transcriptome relative to other subsets. In addition, polarized Tc22 were able to control tumor growth as well as, if not better than, the traditional IFNg-producing Tc1 subset. Tc22s were also found to infiltrate the tumors of human patients with ovarian cancer, comprising up to approximately 30% of expanded CD8 þ tumorinfiltrating lymphocytes (TIL). Importantly, IL22 production in these CD8 þ TILs correlated with improved recurrence-free survival. Given the antitumor properties of Tc22 cells, it may be prudent to polarize T cells to the Tc22 lineage when using chimeric antigen receptor (CAR)-T or T-cell receptor (TCR) transduction-based immunotherapies.

Tc17 biology and function: Novel concepts

“…The authors describe a distinct subtype of CD8 + T cells, termed Tc22, which produced predominantly IL-22, but also IFNγ, TNF-α, IL-2 and IL-17. Adoptive transfers in tumor-bearing mice revealed an antitumorigenic activity of Tc22 cells, while Tc17 displayed rather neutral function, arguing for a unique role of Tc22 versus Tc17 cells in tumor microenvironment [6].…”

“…The main and most studied subpopulation constitutes of cytotoxic T lymphocyte (CTL, Tc1), which can directly kill target cells by release of the cytotoxic molecules perforin and granzymes; in addition, they induce inflammation via secretion of interferon (IFN)-γ and tumor necrosis factor (TNF) [1,2]. However, beside CTLs, other specialized effector subpopulations including follicular cytotoxic T cells (Tfc) [3,4], CD8 + regulatory T cells (CD8 + Treg), Tc2, Tc9, Tc17 and Tc22 cells contribute to effective immune responses [5,6].…”

The Adipocyte and Adaptive Immunity

“…This is a new function for IL-6 in the prevention of viral infection. Furthermore, IL-6 promotes the differentiation of IL-22-producing CD8 + T cells, a CD8 + T cell subset with antitumor function (74).…”

Preclinical and Clinical Immunotherapeutic Strategies in Epithelial Ovarian Cancer

“…In HGSC, CD8 + T-cells’ migratory abilities, through the CXCL9/CXCL10-CXCR3 axis [ 28 ], as well as their tissue residency phenotype, characterized by α E integrin CD103 expression [ 29 , 30 ], were associated with increased survival. St Paul et al demonstrated that IL-22, produced by highly cytotoxic CD8 + TIL, was correlated with improved recurrence-free survival in EOC patients [ 31 ]. Following tumor infiltration, CD8 + TIL performs antitumor effector functions, through the exocytosis of perforin and cytotoxic granzymes, or through the release of interferon (IFN)-γ and tumor necrosis factor (TNF)-α [ 32 ].…”

“…Nonetheless, comprehensive analyses of advanced EOC-associated T-cells revealed that, despite a relatively low number of somatic mutations, the identification of neoepitope-specific CD8 + T-cells is achievable in EOC [ 66 ]. The presence of neoantigen-reactive T-cells in EOC patients was associated with improved survival [ 31 ]. CTA have been extensively studied in EOC, in particular the frequently expressed and highly immunogenic Ag NY-ESO-1.…”