IL-18 Induces PD-1–Dependent Immunosuppression in Cancer

Terme, Magali; Ullrich, Evelyn; Aymeric, Laetitia; Meinhardt, Kathrin; Desbois, Mélanie; Delahaye, Nicolas; Viaud, Sophie; Ryffel, Bernhard; Yagita, Hideo; Kaplanski, Gilles; Prévost-Blondel, Armelle; Kato, Masashi; Schultze, Joachim L.; Tartour, Éric; Kroemer, Guido; Chaput, Nathalie; Zitvogel, Laurence

doi:10.1158/0008-5472.can-11-0993

Cited by 306 publications

(220 citation statements)

References 24 publications

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“…Because basal macrophage activation occurred in PD-1 −/− RAG2 −/− mice, this would suggest that non-T cells, possibly innate lymphoid cells, are responsible for the basal macrophage activation in these mice. For example, PD-1 is expressed on natural killer cells (43) and regulates their cytokine production (44). In the absence of PD-1, natural killer cells may produce more cytokines during immune surveillance or upon infection, possibly affecting the activation status of macrophages.…”

Section: Discussionmentioning

confidence: 99%

Programmed cell death 1 inhibits inflammatory helper T-cell development through controlling the innate immune response

Rui

Honjo

Chikuma

2013

Proc. Natl. Acad. Sci. U.S.A.

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Programmed cell death 1 (PD-1) is an inhibitory coreceptor on immune cells and is essential for self-tolerance because mice genetically lacking PD-1 (PD-1 −/− ) develop spontaneous autoimmune diseases. PD-1 −/− mice are also susceptible to severe experimental autoimmune encephalomyelitis (EAE), characterized by a massive production of effector/memory T cells against myelin autoantigen, the mechanism of which is not fully understood. We found that an increased primary response of PD-1 −/− mice to heat-killed mycobacteria (HKMTB), an adjuvant for EAE, contributed to the enhanced production of T-helper 17 (Th17) cells. Splenocytes from HKMTB-immunized, lymphocyte-deficient PD-1 −/− recombination activating gene (RAG)2 −/− mice were found to drive antigen-specific Th17 cell differentiation more efficiently than splenocytes from HKMTB-immunized PD-1 +/+ RAG2 −/− mice. This result suggested PD-1's involvement in the regulation of innate immune responses. Mice reconstituted with PD-1 −/− RAG2 −/− bone marrow and PD-1 +/+ CD4 + T cells developed more severe EAE compared with the ones reconstituted with PD-1 +/+ RAG2 −/− bone marrow and PD-1 +/+ CD4 + T cells. We found that upon recognition of HKMTB, CD11b + macrophages from PD-1 −/− mice produced very high levels of IL-6, which helped promote naive CD4 + T-cell differentiation into IL-17-producing cells. We propose a model in which PD-1 negatively regulates antimycobacterial responses by suppressing innate immune cells, which in turn prevents autoreactive T-cell priming and differentiation to inflammatory effector T cells.autoimmunity | inflammation

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Section: Discussionmentioning

confidence: 99%

Programmed cell death 1 inhibits inflammatory helper T-cell development through controlling the innate immune response

Rui

Honjo

Chikuma

2013

Proc. Natl. Acad. Sci. U.S.A.

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“…IL-18 produced by tumor cells promotes the development of NK-controlled metastases in a PD-1-dependent manner. Accordingly, PD-1 is expressed by activated mature NK cells in lymphoid organs of tumor bearers and is up regulated by IL-18, as an immunosuppressive cytokine in cancer (Terme et al, 2011). VEGF-D enhanced cell migration is blocked by inhibiting IL-18.…”

Section: Il-18 Enhances Cancer Progressionmentioning

confidence: 99%

Immunotherapeutic Approach for Better Management of Cancer - Role of IL-18

Kuppala¹,

Syed²,

Bandaru³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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Interleukin-18 (IL-18) is an immune-stimulatory cytokine with antitumor activity in preclinical models. It plays pivotal roles in linking inflammatory immune responses and tumor progression and is a useful candidate in gene therapy of lymphoma or lymphoid leukemia. A phase I study of recombinant human IL-18 (rhIL-18) in patients with advanced cancer concluded that rhIL-18 can be safely given in biologically active doses to patients with advanced cancer. Some viruses can induce the secretion of IL-18 for immune evasion. The individual cytokine activity might be potentiated or inhibited by combinations of cytokines. Here we focus on combinational effects of cytokines with IL-18 in cancer progression. IL-18 is an important non-invasive marker suspected of contributing to metastasis. Serum IL-18 may a useful biological marker as independent prognostic factor of survival. In this review we cover roles of IL-18 in immune evasion, metastasis and angiogenesis, applications for chemotherapy and prognostic or diagnostic significance.

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“…It has been shown previously that IL-18, depending on dose or schedule, could either suppress or promote tumor functions in mouse tumor models that involved NK cells (50). In one such model, IL-18 at low doses induced expansion of an immunosuppressive population of Kit þ NK cells expressing programmed cell death ligand 1 (PD-L1), which could be prevented by anti-PD-1 blockade (51).…”

Section: Discussionmentioning

confidence: 99%

Chemoimmunotherapy Using Pegylated Liposomal Doxorubicin and Interleukin-18 in Recurrent Ovarian Cancer: A Phase I Dose-Escalation Study

Simpkins

Flores

Chu

et al. 2013

Cancer Immunology Research

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Recombinant interleukin (IL)-18 (SB-485232) is an immunostimulatory cytokine, with shown antitumor activity in combination with pegylated liposomal doxorubicin (PLD) in preclinical models. This phase I study evaluated the safety, tolerability, and biologic activity of SB-485232 administered in combination with PLD in subjects with recurrent ovarian cancer. The protocol comprised four cycles of PLD (40 mg/m 2 ) on day 1 every 28 days, in combination with SB-485232 at increasing doses (1, 3, 10, 30, and 100 mg/kg) on days 2 and 9 of each cycle, to be administered over five subject cohorts, followed by discretionary PLD monotherapy. Sixteen subjects were enrolled. One subject withdrew due to PLD hypersensitivity. Most subjects (82%) were platinum-resistant or refractory, and had received a median of three or more prior chemotherapy regimens. SB-485232 up to 100 mg/kg with PLD had an acceptable safety profile. Common drug-related adverse events were grade 1 or 2 (no grade 4 or 5 adverse events). Concomitant PLD administration did not attenuate the biologic activity of IL-18, with maximal SB-485232 biologic activity already observed at 3 mg/kg. Ten of 16 enrolled subjects (63%) completed treatment, whereas five (31%) subjects progressed on treatment. A 6% partial objective response rate and a 38% stable disease rate were observed. We provide pilot data suggesting that SB-485232 at the 3 mg/kg dose level in combination with PLD is safe and biologically active. This combination warrants further study in a phase II trial. Cancer Immunol Res; 1(3); 168-78. Ó2013 AACR.

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IL-18 Induces PD-1–Dependent Immunosuppression in Cancer

Cited by 306 publications

References 24 publications

Programmed cell death 1 inhibits inflammatory helper T-cell development through controlling the innate immune response

Programmed cell death 1 inhibits inflammatory helper T-cell development through controlling the innate immune response

Immunotherapeutic Approach for Better Management of Cancer - Role of IL-18

Chemoimmunotherapy Using Pegylated Liposomal Doxorubicin and Interleukin-18 in Recurrent Ovarian Cancer: A Phase I Dose-Escalation Study

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