PD-1 modulates regulatory T-cell homeostasis during low-dose interleukin-2 therapy

Asano, Takeru; Meguri, Yusuke; Yoshioka, Tomoko; Kishi, Yoshiki; Iwamoto, Miki; Nakamura, Makoto; Sando, Yasuhisa; Yagita, Hideo; Koreth, John; Kim, Haesook T.; Alyea, Edwin P.; Armand, Philippe; Cutler, Corey; Ho, Vincent T.; Antin, Joseph H.; Soiffer, Robert J.; Maeda, Yoshinobu; Tanimoto, Mitsune; Ritz, Jérôme; Matsuoka, Ken

doi:10.1182/blood-2016-09-741629

Cited by 154 publications

(133 citation statements)

References 59 publications

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“…The PD‐1/PD‐L1 axis might regulate the activation of naïve Treg by APC, and thus anti‐PD‐1 treatment could affect the induction of these cells. In the IL‐2‐induced chronic graft‐versus‐host disease (cGVHD) mouse model, concomitant administration of low‐dose IL‐2 and anti‐PD‐1 antibody has been found to induce an increase in peripheral blood Treg and amelioration of cGVHD in 1 week . Consistent with this, we observed that the proportion of peripheral blood effector Treg after 2 courses of anti‐PD‐1 therapy in the present study also increased.…”

Section: Discussionsupporting

confidence: 88%

Activation of central/effector memory T cells and T‐helper 1 polarization in malignant melanoma patients treated with anti‐programmed death‐1 antibody

et al. 2018

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Human anti‐programmed death‐1 (PD‐1) antibody possesses the capability to revitalize host T cells and has been an effective therapy for metastatic malignant melanoma (MM). The precise subsets of T cells predominantly activated by anti‐PD‐1, however, have not yet been clarified. In this study, peripheral blood mononuclear cells obtained from MM patients scheduled to receive anti‐PD‐1 (nivolumab) therapy, and healthy subjects (HS), were systematically examined on flow cytometry to identify changes in the proportion of immune cell subsets. Compared with HS, MM patients prior to therapy had an increased proportion of activated CD8+ T cells with effector memory phenotypes (Tem), and PD‐1 positive subsets of CD4+ central memory T cells (Tcm) and T‐helper (Th)17 cells. After a single course of anti‐PD‐1 therapy, MM patients had an increase in activated Tem and Tcm subsets of CD4+ and CD8+ T cells, and activated Th1 plus T‐helper follicular 1 cells. There was no consistent change in the proportion of Tfh cells, B cells, natural killer cells, or dendritic cells. The observed activated phenotypes were attenuated during the course of therapy, but regulatory T cells belonging to the CD3+CD4+CD45RO+CD25high fraction increased at disease progression. Taken together, anti‐PD‐1 therapy modulates systemic immune reactions and exerts anti‐tumor effects, not only by revitalizing Tem and Tcm of CD4+ and CD8+ T cells, but also via a shift to a Th1 phenotype.

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Section: Discussionsupporting

confidence: 88%

Activation of central/effector memory T cells and T‐helper 1 polarization in malignant melanoma patients treated with anti‐programmed death‐1 antibody

et al. 2018

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“…PD1 plays a crucial role in Treg cell homeostasis and survival as IL‐2 stimulation with PD1 blockade or genetic deletion of PD1 resulted in an overt proliferation of Treg cells followed by a rapid contraction due to increased apoptosis . A recent study reported that apoptotic intratumoral Treg cells express a low level of PD1 (PD1 lo ) whereas viable intratumoral Treg cells showed enhanced PD1 expression (PD1 hi ).…”

Section: Inhibitory Receptorsmentioning

confidence: 99%

Intratumoral regulatory T cells: markers, subsets and their impact on anti‐tumor immunity

et al. 2019

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Summary Regulatory T (Treg) cells play a crucial role in maintaining self‐tolerance and resolution of immune responses by employing multifaceted immunoregulatory mechanisms. However, Treg cells readily infiltrate into the tumor microenvironment (TME) and dampen anti‐tumor immune responses, thereby becoming a barrier to effective cancer immunotherapy. There has been a substantial expansion in the development of novel immunotherapies targeting various inhibitory receptors (IRs), such as CTLA4, PD1 and LAG3, but these approaches have mechanistically focused on the elicitation of anti‐tumor responses. However, enhanced inflammation in the TME could also play a detrimental role by facilitating the recruitment, stability and function of Treg cells by up‐regulating chemokines that promote Treg cell migration, and/or increasing inhibitory cytokine production. Furthermore, IR blockade may enhance Treg cell function and survival, thereby serving as a resistance mechanism against effective immunotherapy. Given that Treg cells are comprised of functionally and phenotypically heterogeneous sub‐populations that may alter their characteristics in a context‐dependent manner, it is critical to identify unique molecular pathways that are preferentially used by intratumoral Treg cells. In this review, we discuss markers that serve to identify certain Treg cell subsets, distinguished by chemokine receptors, IRs and cytokines that facilitate their migration, stability and function in the TME. We also discuss how these Treg cell subsets correlate with the clinical outcome of patients with various types of cancer and how they may serve as potential TME‐specific targets for novel cancer immunotherapies.

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“…We recently demonstrated that PD-1 is a critical homeostatic regulator for Treg by modulating proliferation and apoptosis during IL-2 therapy [39]. This study showed that exogenous IL-2 promptly induces the expression of PD-1 particularly on central-memory Tregs and increased PD-1 expression was maintained during IL-2 therapy.…”

Section: Low-dose Il-2 Combined With Checkpoint Blockadementioning

confidence: 68%

Low-dose interleukin-2 as a modulator of Treg homeostasis after HSCT: current understanding and future perspectives

Matsuoka

2017

Int J Hematol

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CD4 + CD25 + Foxp3 + Treg is a functionally distinct subset of mature T cells with broad suppressive activity and has been shown to play an important role in the establishment of immune tolerance after HSCT. Altered cytokine environment in post-HSCT lymphopenia with a relative functional deficiency of IL-2 could hamper the reconstitution of Treg, leading to refractory GVHD. Based on the theory of low-dose IL-2 in which Treg can be selectively stimulated through the high-affinity IL-2 receptor, clinical studies have been conducted and demonstrated that low-dose IL-2 administration can restore Treg homeostasis and promote the expansion of this subset on the polymorphic processes of Treg reconstitution after HSCT. The new therapeutic indication of IL-2 for immune tolerance has launched in the field of HSCT and is spreading to the other fields including the treatment for autoimmune diseases. To further extend the indication of low-dose IL-2 to more patients with various immunological problems, the optimization of the timing and dosing of IL-2 intervention and the concomitant immune suppressive therapy according to each patient-based assessment are to be desired in the near future. Further prospective studies may facilitate the development of novel therapeutic algorithms for the effective and safe induction of immune tolerance after HSCT.

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PD-1 modulates regulatory T-cell homeostasis during low-dose interleukin-2 therapy

Abstract: Key Points IL-2 induces expression of PD-1 on Tregs, and PD-1 blockade promotes Treg differentiation and apoptosis. PD-1 regulates IL-2–induced Treg proliferation and prolongs Treg survival in murine models and in patients receiving low-dose IL-2 therapy.

Cited by 154 publications

References 59 publications

Activation of central/effector memory T cells and T‐helper 1 polarization in malignant melanoma patients treated with anti‐programmed death‐1 antibody

Activation of central/effector memory T cells and T‐helper 1 polarization in malignant melanoma patients treated with anti‐programmed death‐1 antibody

Intratumoral regulatory T cells: markers, subsets and their impact on anti‐tumor immunity

Low-dose interleukin-2 as a modulator of Treg homeostasis after HSCT: current understanding and future perspectives

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