IL-2-driven CD8+ T cell phenotypes: implications for immunotherapy

The therapeutic potential of interleukin (IL)-2 in cancer and chronic infections has triggered the development of novel IL-2-based biologicals and combinatorial treatment strategies to achieve high efficacy and low off-target adverse effects in mouse models, before being tested in clinical trials.Suboptimal IL-2 variants fused to an anti-PD-1 antibody specifically promote robust therapeutic effects in various preclinical cancer and infection mouse models (e.g., implanted lymphoma, pancreatic adenocarcinoma, glioma, colon carcinoma, spontaneous pancreatic cancer, and chronic viral infection). The effect occurs by targeting IL-2 to PD-1+ T cells and enhancing IL-2 binding to an ‘intermediate-affinity IL-2 receptor’ in cis.Strong IL-2 signals are required to induce the formation of a unique differentiation state of antigen-stimulated CD8+ T cells, termed ‘better effectors’, with superior antitumor and antiviral properties in mice.Based on preclinical mouse models, we propose that regulatory T cells suppress CD8+ T cells and the formation of ‘better effectors’ via IL-2 sequestration, which is disabled upon administration of exogenous IL-2-based biologicals. Strong IL-2 receptor stimulation of antigen-activated CD8+ T cells induces a unique gene expression program in which the cells harbor a superior cytotoxicity and anticancer/antiviral potential. This effect can be achieved by exogenous IL-2-based therapy or depletion of Tregs. Recent progress in the design of targeted IL-2-derived biologicals and single cell transcriptomics provide a novel framework for the development of putative therapies for treating cancer and chronic infections in humans. The therapeutic potential of interleukin (IL)-2 in cancer treatment has been known for decades, yet its widespread adoption in clinical practice remains limited. Recently, chimeric proteins of an anti-PD-1 antibody and suboptimal IL-2 variants were shown to stimulate potent antitumor and antiviral immunity by inducing unique effector CD8+ T cells in mice. A similar subset of cytotoxic T cells is induced by depletion of regulatory T cells (Tregs), suggesting IL-2 sequestration as a major mechanism through which regulatory T cells suppress activated CD8+ T cells. Here, we present our view of how IL-2-based biologicals can boost the antitumor response at a cellular level, and propose that the role of Tregs following such treatments may have been previously overestimated. The therapeutic potential of interleukin (IL)-2 in