Distinct populations of IL-10– and IL-35–producing Treg cells in the tumor microenvironment cooperatively promote upregulation of BLIMP1 and exhaustion of tumor-infiltrating conventional T cells. Distinct populations of IL-10– and IL-35–producing Treg cells in the tumor microenvironment cooperatively promote upregulation of BLIMP1 and exhaustion of tumor-infiltrating conventional T cells. CITATION Sawant DV, Yano H, Chikina M, et al. Adaptive plasticity of IL-10+ and IL-35+ Treg cells cooperatively promotes tumor T cell exhaustion. Nat Immunol. 2019;20(6):724-735. FoxP3+ regulatory T cells (Tregs) are key mediators of self-tolerance and can therapeutically induce tolerance to transplanted organs. Tregs utilize multiple mechanisms to suppress activity of conventional T cells (Tconvs), including metabolic disruption of target cells, surface expression of inhibitory molecules, and secretion of immunosuppressive cytokines, such as interleukin (IL)-10, transforming growth factor (TGF)-β and IL-35. By suppressing self- or donor-reactive Tconvs, Tregs prevent pathological immune responses. However, these suppressive functions become harmful when Tregs inhibit antitumor immunity. Broadly disrupting Treg function in cancer patients to unleash antitumor immunity carries a risk of severe autoimmune complications. Thus, recent work has sought to identify and disrupt suppressive mechanisms employed by Tregs specifically within the tumor microenvironment (TME). Indeed, Tregs have been shown to use specific suppressive mechanisms in a tissue- and context-dependent manner, and, within a particular tissue, Tregs have heterogeneous functional profiles. Sawant and colleagues reveal that within the TME, IL-10 and IL-35 production are segregated into distinct Treg subtypes and the production of both of these cytokines by Tregs is required to maximally promote BLIMP1 expression and exhaustion in tumor-infiltrating Tconvs. Using mice engineered to indicate the expression of FoxP3, IL-10 and a subunit of IL-35 (Ebi3), the authors determined that distinct populations of FoxP3+ cells produced IL-10 and IL-35, with very few cells producing both cytokines simultaneously. This was evident in Tregs isolated from mouse lymph nodes, tumors and lungs as well as human peripheral blood and tumors. While both IL-10– and IL-35–producing Tregs were enriched in the TME compared with tumor-draining lymph nodes, IL-35–producing T cells were the most enriched, suggesting that targeting IL-35–producing Tregs may specifically disrupt immune evasion by the tumor without promoting severe autoimmunity. Both subsets exhibited the ability to interconvert after stimulation in vitro, although more work is needed to determine whether they exhibit plasticity in vivo and which signals direct cells to develop into either subset. To determine the functional role of each Treg subset, the authors used mice with conditional deletion of IL-10 or Ebi3 in FoxP3+ cells. Treg-specific deletion of either cytokine resulted in similarly reduced tumor growth and a decrease in inhibitory receptor (PD-1, TIM3, LAG3, TIGIT and 2B4) expression in tumor-infiltrating Tconvs. Interestingly, the combined conditional deletion of both cytokines did not further reduce tumor growth, indicating that Treg-derived IL-10 and IL-35 play partially overlapping noncompensatory roles in promoting tumor growth. As for cytokine-specific functions, IL-35 better promoted inhibitory receptor expression and reduced differentiation into central memory cells among tumor-infiltrating CD4+ and CD8+ Tconvs, while only IL-10 modestly suppressed effector cytokine production. Both IL-10 and IL-35 contributed to an exhausted transcriptional signature in tumor-infiltrating CD8+ T cells, including upregulation of Prdm1 (BLIMP1) expression in PD1hi TIM3+ tumor-infiltrating cells. The authors found that mediators of IL-35 signaling (STAT1 and STAT4), and to a lesser extent IL-10 signaling (STAT3), exhibited greater binding to the Prdm1 locus in CD8+ T cells after in vitro stimulation, suggesting that these cytokines promote Tconv exhaustion by cooperatively promoting Prdm1 expression. Prdm1 did appear to play a critical role in Tconv exhaustion, because deletion of one Prdm1 allele in CD8+ T cells was associated with reduced expression of inhibitory receptors in tumor-infiltrating cells as well as slower tumor growth. Whether modulation of BLIMP1 expression is the main mechanism of IL-10 and IL-35 promotion of tumor growth and immune evasion remains to be determined. In transplantation, induction of allospecific Tregs and dysfunction of allospecific Tconvs have been associated with a state of donor-specific tolerance. Adoptive transfer of Tregs is under investigation for use as an immunosuppressive therapy in transplant recipients as well as patients with autoimmune diseases, with studies seeking to optimize the suppressive function of transferred cells. The study of Sawant et al. suggests that multiple subsets of Tregs, including both IL-10– and IL-35–producing cells, may play different roles. Likewise, strategies for allospecific Treg induction may be most beneficial if they induce multiple subsets of Tregs.
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May 1, 2020
Rafael Sanguinetti Czepielewski + 10
Open Access