Immune regulation and cytotoxic T cell activation of IL-10 agonists - Preclinical and clinical experience

Abstract

The expansion and activation of tumor antigen reactive CD8⁺ T cells are primary goals of immunotherapies for cancer. IL-10 is an anti-inflammatory cytokine with an essential role in the development and proliferation of regulatory T cells, restricting myeloid and chronic inflammatory T cell responses. However, IL-10 is also essential for the expansion of antigen activated, tumor specific CD8⁺ T cells, leading to spontaneous tumor development in IL-10 deficient patients and mice. IL-10 induces IFNγ and cytotoxic mediators in antigen activated T cells. In clinical trials, monotherapy with recombinant, pegylated IL-10 (Pegilodecakin) induced objective responses in cancer patients. Patients receiving pegilodecakin had a systemic increase of IFNγ and granzymes, proliferation and expansion of immune checkpoint positive CD8⁺ T cells. Combination of pegilodecakin with anti-PD-1 appeared to improve on the efficacy of the single agents.

Keywords: CD8 T cell cytotoxicity; Pegylated IL-10; T cell invigoration clinical trial; Tumour immunology.

Fig. 1

IL-10 at the crossroad from inflammation to the stimulation of CD8⁺ T cells. A). Toll like Receptors (TLR) or pattern recognition (PRR) mediated inflammatory responses induce the expression of IL-12 and IL-23 . IL-10 activates STAT3 which inhibits expression of the shared p40 subunit of IL-12 and IL-23. IL-10 also inhibits inflammatory Th17 Cells directly and indirectly through the stimulation of Tregs. Suppression of IL-17, IL-1 and TNFa inhibit neutrophil and macrophage activation in tumor associated inflammation and inflammatory diseases. B). Upon antigen stimulation, CD8⁺ T cells upregulate the IL-10 receptor and IL-10. Autocrine and therapeutic IL-10 increases anti-apoptotic signals and IFNγ in those antigen experienced CD8⁺ T cells. IFNγ is released once the CD8⁺ T cell is recognizing the antigen (MHC + TAA) on tumor cells or dendritic cells (DC) in the tumor. This localized IFNγ release, leads to MHC I and MHC II upregulation in the tumor and enables tumor centric priming of CD4⁺ and CD8⁺ T cells. C). Pegilodecakin induces directly IFNγ, Granzyme and FasL expression in antigen activated CD8⁺ T cells, facilitating the upregulation of MHC I on the tumor cell and induction of tumor cell killing.

Fig. 2

Expansion of the most fitting – Pegilodecakin expands predominantly tumor recognizing CD8 + T cells. Antigen recognition upregulates IL-10Ra on CD8⁺ T cells. Pegilodecakin selects preferentially CD8⁺ T cells, which had a recent antigen encounter - by virtue of their IL-10Ra^hi status. IL-10 signaling leads to increased activation, survival and expansion of these TAA reactive CD8⁺ T cells. In contrast, IL-2 or IL-15, induce proliferation and activation of CD4⁺ and CD8⁺ T cells independent of a TCR signal and NK cells. This leads to the activation and proliferation of a large proportion of all peripheral T cells, irrespective of antigen specificity.