The Inducible Costimulator Augments Tc17 Cell Responses to Self and Tumor Tissue

Abstract

The inducible costimulator (ICOS) plays a key role in CD4+ Th17 cell development, but its role in CD8+ Tc17 cell development and self/tumor immunity remains unknown. We found that ICOS co-stimulation was important for the functional maintenance but not differentiation of Tc17 cells in vitro. Blocking the ICOS pathway using an antagonist antibody or by using mice genetically deficient in the ICOS ligand (ICOSL) reduced the antitumor activity of adoptively transferred Tc17 cells. Conversely, activating Tc17 cells with an ICOS agonist in vitro enhanced their capacity to eradicate melanoma and induce autoimmune vitiligo when infused into mice. However, ICOS stimulation did not augment the antitumor activity of IL-2 expanded T cells. Additional investigation revealed that ICOS stimulation not only increased IL-2Rα, CXCR3 and IL-23R expression on Tc17 cells, but also dampened their expression of suppressive molecule CD39. Although Tc17 cells activated with an ICOS agonist co-secreted heightened IL-17A, IL-9 and IFN-γ, their therapeutic effectiveness was critically dependent on IFN-γ production. Depletion of IL-17A and IL-9 had little impact of antitumor Tc17 cells activated with an ICOS agonist. Collectively, our work reveals that the ICOS pathway potentiates the antitumor activity of adoptively transferred Tc17 cells. This work has major implications for the design of vaccine, antibody and cell-based therapies for autoimmunity, infectious disease and cancer.

Proteomics analysis reveals a Th17-prone cell population in presymptomatic graft-versus-host disease

“…Based on this finding, it would be interesting to determine if patients with GI-GVHD have antigen-presenting cells (APCs) that express ligands for ICOS and CD28 on their cell surface and if it is due to host preconditioning, cytokine release, alloreactivity, and perhaps the microbiome. Indeed, host preconditioning with total body irradiation was recently shown to induce ICOS ligand expression on APCs (59). This requires further exploration in experimental models, given that studying recipient antigen presentation in patients is difficult (beyond correlative studies that are imperfect).…”

“…The fourth potential target is the ICOS/ICOS ligand pathway, which can be blocked by anti-ICOS inhibitors. Anti–murine-ICOS has been successfully used to alleviate murine GVHD (66) and a syngeneic mouse model of melanoma transplanted with Tc17 (59). Different clones of anti–human-ICOS have been successfully used to ameliorate GVHD in SCID mice grafted with human PBMCs (67) and in the context of tumoral microenvironment (68).…”

Exploiting IL-17-producing CD4+ and CD8+ T cells to improve cancer immunotherapy in the clinic

“…In contrast to the work in NSG models, ICOS does not merely augment IL-17A and IFN-γ production and expansion of Th17 cells but also bolsters CD8 + Tc17 cells as well [120]. Using mice deficient in ICOS or the ICOS ligand, ICOS was found to support Tc17 cell responses to tumors.…”

The role of IL-17 in vitiligo: A review

“…Infusion of an ICOS agonist has been reported to enhance the capacity to induce autoimmune vitiligo compared to an IgG control (p=0.003), while infusion of an ICOS antagonist impairs the capacity to induce autoimmune vitiligo (p<0.05)[69]. …”