Interleukin-2 and PD-1 synergistically modify T cell exhaustion programs

CITATIONS Hashimoto M, Araki K, Cardenas MA, et al. PD-1 combination therapy with IL-2 modifies CD8+ T cell exhaustion program. Nature. 2022; 610(7930):173-181. Codarri Deak L, Nicolini V, Hashimoto M, et al. PD-1-cis IL-2R agonism yields better effectors from stem-like CD8+ T cells. Nature. 2022; 610(7930):161-172. T cells often become exhausted in response to persistent antigen stimulation in models of chronic infections, tumor, and organ transplantation. Exhausted T cells tend to lose their proliferative capacity and effector functions, and eventually die of apoptosis. In patients with cancer, the checkpoint inhibitor PD-1 is functionally involved in T cell exhaustion because therapeutically blocking PD-1 has been shown to reinvigorate exhausted T cells and improve the outcome in patients with cancer. However, only a fraction of the patients with cancer respond to PD-1 blockade, thus prompting a vigorous search for other pathways that can improve the efficacy of PD-1 targeted therapies. Two recent papers in Nature, one by Hashimoto et al and the other by Codarri Deak et al, show that interleukin (IL)-2 markedly improves the therapeutic efficacy of PD-1 blockade in models of tumors and chronic lymphocytic choriomeningitis virus infection in mouse. This improved efficacy is because of the activation of PD-1+ T Cell Factor-1+ (TCF1+) stem-like CD8+ T cells that constantly replenish the T effector pool in those chronic conditions. Importantly, the terminally exhausted T cells are neither responsive to IL-2 nor PD-1 blockade monotherapy. Mechanistically, combined IL-2 and PD-1-targeted therapy appears to alter the differentiation program of stem-like CD8+ T cells, resulting in the generation of transcriptionally and epigenetically distinct CD8+ T cells that resemble highly functional CD8+ T effectors. After the combined therapy, the reinvigorated CD8+ T cells express high levels of CXCR3, the receptor for CXCL9 and CXCL10, chemokines that are important for T cell migration into target tissues. The role of IL-2 in those models is intriguing. It is well known that IL-2 is a critical cytokine in both T cell immunity and immune tolerance. The receptor for IL-2 (IL-2R) consists of 3 chains, the alpha (CD25), beta (CD122), and gamma (CD132) chain, and besides CD8+ T effector cells, Foxp3+ regulatory T cells (TES), a cell type required for tolerance, also express the IL-2R. As a result, there is strong interest in using low-dose IL-2 to preferentially target the IL-2R on Tregs, thereby expanding Tregs to promote tolerance in transplantation and autoimmunity. As opposed to T effector cells, however, Tregs constitutively express high levels of CD25. An engineered IL-2 variant (IL-2v) that selectively engages CD122 and CD132 on T effector cells, thus limiting Treg expansion, has been tested in cancer immunotherapy models. These experiments suggested that the expansion of CD8+ T effector cells required the synergy of IL-2 binding to CD25 and PD-1 blockade. Interruption of IL-2 binding to CD25 using, for example, a nondepleting anti-CD25 mAb abrogated expansion of CD8+ T effector cells. These findings may help explain the disappointing results from cancer clinical trials using anti–PD-1 antibodies in combination with modified or genetically engineered forms of IL-2 that do not bind to CD25. Importantly, studies from Codarri Deak et al described a recombinant reagent PD-1–IL-2v, a new immunocytokine that overcomes the need for CD25 binding by docking IL-2v onto PD-1 on the same T cell (in cis). Cis binding of PD-1–IL-2v to PD-1, CD122, and CD132 simultaneously restored the ability of stem-like CD8+ T cells to differentiate into potent T effector cells in the absence of CD25 binding in models of chronic infection and cancer (Fig. 1). These results are highly relevant to transplant research as exhaustion arises during chronic exposure to alloantigens and transplant recipients with high levels of circulating exhausted T cells have better graft function, suggesting that exhaustion may represent a mechanism of peripheral allograft tolerance. In fact, in organ transplant recipients with cancer, immunotherapies, including PD-1 blockade therapies, often result in acute allograft rejection. However, in contrast with the cancer treatment setting, in which the aim is to reverse T cell exhaustion, promoting exhaustion of alloreactive T cells is a sought-after goal to improve transplant outcomes. In some clinical settings, nondepleting anti-CD25 antibodies are used as induction therapy to inhibit effector T cells early after transplantation. Findings from these new studies support the hypothesis that prolonged anti-CD25 treatment may help prevent graft rejection by inhibiting alloreactive PD-1+ TCF1+ stem-like CD8+ T cells, especially in patients with preformed allospecific CD8+ T cells. Less is clear on how these new data may affect trials testing IL-2 therapy to expand Tregs. In both papers, IL-2 increased antivirus and anticancer effector T cells only when combined with anti–PD-1 therapy. This result suggests a possibility that IL-2 may expand Tregs without affecting PD-1+ TCF1+ stem-like CD8+ T cells, but this possibility must be carefully tested in transplant recipients receiving IL-2R targeting therapies to promote Treg expansion.