Harnessing CD8 T cell responses using PD-1-IL-2 combination therapy

Abstract

There is considerable interest in developing more effective programmed cell death (PD)-1 combination therapies against cancer. One major obstacle to these efforts is a dysfunctional/exhausted state of CD8 T cells, which PD-1 monotherapy is not able to overcome. Recent studies have highlighted that PD-1⁺ T cell factor (TCF)-1⁺ stem-like CD8 T cells are not fate locked into the exhaustion program and their differentiation trajectory can be changed by interleukin (IL)-2 signals. Modifying the CD8 T cell exhaustion program and generating better effectors from stem-like CD8 T cells by IL-2 form the fundamental immunological basis for combining IL-2 with PD-1 therapy. Many versions of IL-2-based products are being tested and each product should be carefully evaluated for its ability to modulate dysfunctional states of anti-tumor CD8 T cells.

Keywords: IL-2; PD-1; T cell exhaustion; cancer; chronic infection; immunotherapy.

Figure 1.. CD8 T cell states under chronic antigen stimulation.

Differentiation trajectory of three CD8 T cell subsets from quiescent (stem-like) to transitory effector-like to terminally differentiated (exhausted) states during cancer and chronic infection. Three CD8 T cell subsets are distinct from each other in terms of generation/maintenance, proliferative capacity, molecular signature, and location. Created with BioRender.com.

Figure 2.. IL-2/IL-2R system.

IL-2 signals through two specific receptors formed by combinations of three IL-2R subunits: heterodimeric intermediate-affinity (Kd ~ 10⁻⁹ M) receptor, consisted of the IL-2Rβ and γc, and heterotrimeric high-affinity (Kd ~ 10⁻¹¹ M) receptor formed by IL-2Rα, IL-2Rβ, and γc. Both heterodimeric and heterotrimeric receptors signal through interaction of the intracellular domains of IL-2Rβ and γc with Janus kinase 1 (JAK1) and JAK3, respectively. Intermediate-affinity IL-2R is expressed in broad cell types including memory phenotype CD8 T cells, NK cells, and NKT cells. IL-2R, Interleukin-2 receptor; NK, natural killer; γc, common γ chain. Created with BioRender.com.

Figure 3.. PD-1 + IL-2 combination therapy generates qualitatively superior CD8 T cells, which resemble functional effector CD8 T cells seen during an acute infection.

Differentiation trajectory of CD8 T cells during PD-1 + IL-2 combination therapy vs. untreated or PD-1 therapy. PD-1+TCF-1+ stem-like CD8 T cells are not fate-locked into the exhaustion program and their differentiation trajectory can be changed by IL-2 signals, resulting in generation of acute-like highly functional effector CD8 T cells. Created with BioRender.com.

Figure 4.. IL-2 wild-type (IL-2wt) and modified IL-2 that does not bind CD25 (IL-2v) work differently in vivo during cancer and chronic infection.

(A) Differential usage of IL-2R system by IL-2 wild-type (IL-2wt) and IL-2 variant (IL-2v) that does not bind CD25 but still binds CD122 and CD132. IL-2wt can deliver IL-2 signals to target cells either through heterodimeric intermediate-affinity IL-2R or heterotrimeric high-affinity IL-2R, whereas IL-2v transmits signals only through heterodimeric intermediate-affinity IL-2R. (B) Antigens together with IL-2wt signals delivered to antigen-specific stem-like CD8 T cells induce the formation of heterotrimeric high-affinity IL-2 receptor (IL-2R) during cancer and chronic infection. High-affinity IL-2R expressing antigen-specific CD8 T cells selectively capture limited source of IL-2wt and undergo extensive proliferation and effector differentiation. IL-2wt availability is limited for non-antigen-specific CD8+ T cells because a given antigen is not present and they do not upregulate CD25. (C) Bystander CD8 T cells can ustilize IL-2v through intermediate-affinity IL-2R, so IL-2v is soaked up by bystander CD8 T cells, which comprise majority of CD8 T cells in vivo. IL-2R, Interleukin-2 receptor; γc, common γ chain. Created with BioRender.com.