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A PD-1-targeted, receptor-masked IL-2 immunocytokine that engages IL-2Rα strengthens T cell-mediated anti-tumor therapies

ABSTRACT: A PD-1-targeted, receptor-masked IL-2 immunocytokine that engages IL-2Rα strengthens T cell-mediated anti-tumor therapies

PROVIDER: PRJNA1052664 | ENA |

REPOSITORIES: ENA

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			Action	DRS
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	SRR27215600_1.fastq.gz	Fastqsanger.gz
	SRR27215600_2.fastq.gz	Fastqsanger.gz
	SRR27215617_1.fastq.gz	Fastqsanger.gz
	SRR27215617_2.fastq.gz	Fastqsanger.gz

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A PD-1-targeted, receptor-masked IL-2 immunocytokine that engages IL-2Rα strengthens T cell-mediated anti-tumor therapies

Project description:IL-2 is a cytokine approved for the treatment of melanoma and renal cell carcinoma and induced complete, durable tumor regression in some patients. However, its broader use in cancer immunotherapy has been limited by severe toxicity. A new generation of IL-2 therapies with decreased binding to IL-2 receptor alpha chain (IL-2Rα), intended to mitigate toxicity and Treg expansion, are being developed. However to date these have had limited clinical success. Here, we demonstrate that the ability to engage IL-2Rα is critical for the anti-tumor activity of a systemic IL-2 therapy. Despite inducing systemic expansion of CD8+ T cells and NK cells over Tregs, an IL-2 mutein with abolished IL-2Rα binding demonstrated limited anti-tumor efficacy compared to wild-type IL-2. Based on these findings, we developed a PD-1-targeted, receptor-masked IL-2 immunocytokine, PD1-IL2Ra-IL2, with attenuated systemic IL-2 activity but maintained the capacity to engage IL-2Rα on PD-1+ T cells. PD1-IL2Ra-IL2 (REGN10597) shows PD-1-targeting-dependent IL-2 activity in vitro and drives selective expansion of tumor-infiltrating PD-1+ CD8+ T cells with vigorous effector profiles in vivo. PD1-IL2Ra-IL2 treated mice displayed no signs of systemic toxicities observed with unmasked IL-2 treatment, yet achieved robust tumor growth control. Finally, we demonstrate that PD1-IL2Ra-IL2 can be effectively combined with several other T cell-mediated immunotherapies (anti-PD-1, CD3 bispecific antibodies, and CAR-T cells) to potentiate antitumor responses. Collectively, these results provide unique insights into the functional mechanism of IL-2 based therapeutics and highlight the therapeutic potential of PD1-IL2Ra-IL2 as a novel targeted, receptor masked, and “α-maintained” IL-2 therapy for cancer treatment.

2024-08-22 | GSE250205 | GEO

A PD-1-targeted, receptor-masked IL-2 immunocytokine that engages IL-2Rα strengthens T cell-mediated anti-tumor therapies.

Project description:The clinical use of interleukin-2 (IL-2) for cancer immunotherapy is limited by severe toxicity. Emerging IL-2 therapies with reduced IL-2 receptor alpha (IL-2Rα) binding aim to mitigate toxicity and regulatory T cell (Treg) expansion but have had limited clinical success. Here, we show that IL-2Rα engagement is critical for the anti-tumor activity of systemic IL-2 therapy. A "non-α" IL-2 mutein induces systemic expansion of CD8+ T cells and natural killer (NK) cells over Tregs but exhibits limited anti-tumor efficacy. We develop a programmed cell death protein 1 (PD-1)-targeted, receptor-masked IL-2 immunocytokine, PD1-IL2Ra-IL2, which attenuates systemic IL-2 activity while maintaining the capacity to engage IL-2Rα on PD-1+ T cells. Mice treated with PD1-IL2Ra-IL2 show no systemic toxicities observed with unmasked IL-2 treatment yet achieve robust tumor growth control. Furthermore, PD1-IL2Ra-IL2 can be effectively combined with other T cell-mediated immunotherapies to enhance anti-tumor responses. These findings highlight the therapeutic potential of PD1-IL2Ra-IL2 as a targeted, receptor-masked, and "α-maintained" IL-2 therapy for cancer.

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RNA-sequencing of livers from p40-/-IL-2Rα-/- PBC mouse model and control.

Project description:We performed RNA sequencing of liver transcriptome from 12-week-old p40-/-IL-2Rα-/- (a mouse model of primary biliary cholangitis) and littermate p40-/-IL-2Ra+/- (control) mice.

2021-09-16 | GSE184066 | GEO

IL-2Rα is Dispensable for Murine B Cell Development and Humoral Response

Project description:The cytokine IL-2 plays a pivotal role in the immune system, specifically in the proliferation of T, B, and NK cells. The alpha subunit of the IL-2 receptor, IL-2Rα (CD25), is known to regulate the expansion and differentiation of T lymphocytes. CD25 is also expressed in developing B cells; however, its B cell intrinsic role remains undefined. We generated a mouse model with a B cell-specific deletion of CD25 to ascertain its role in B cell development and function. Unexpectedly, we found that the loss of CD25 had no impact on B cell development, homeostasis, or immune response to model antigens. Additionally, while CD25 expression was upregulated in activated splenic B cells, its absence did not affect class switch recombination in vitro or in vivo. We conclude that in contrast to its critical role in T cell differentiation and function, and despite its expression in developing and activated B cells, CD25 does not have any significant role in B cell development and adaptive immune functions.

2025-05-07 | GSE282135 | GEO

IL-2Rα is Dispensable for Murine B Cell Development and Humoral Response

Project description:IL-2Rα is Dispensable for Murine B Cell Development and Humoral Response

| PRJNA1187268 | ENA

RNA-sequencing of livers from p40-/-IL-2Rα-/- PBC mouse model and control.

Project description:RNA-sequencing of livers from p40-/-IL-2Rα-/- PBC mouse model and control.

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β-glucans are Masked but Contribute to Pulmonary Inflammation During Pneumocystis Pneumonia

Project description:β-glucans, which can activate innate immune responses, are a major component in the cell wall of the cyst form of Pneumocystis. In the current study we examined whether β-1,3 glucans are masked by surface proteins in Pneumocystis, and what role β-glucans play in Pneumocystis-associated inflammation. For 3 species, including P. jirovecii, which causes Pneumocystis pneumonia (PCP) in humans, P. carinii, and P. murina, β-1,3 glucans were masked in most organisms, as demonstrated by increased exposure following trypsin treatment. Using Q-PCR and microarray techniques, we demonstrated in a mouse model of PCP that treatment with caspofungin, an inhibitor of β-1,3 glucan synthesis, for 21 days, decreased expression of a broad panel of inflammatory markers, including IFN-γ, TNF-α, IL-1β, IL-6, and multiple chemokines/chemokine ligands. Thus, β-glucans in Pneumocystis cysts are largely masked, which likely decreases innate immune activation; this mechanism presumably was developed for interactions with immunocompetent hosts, in whom organism loads are substantially lower. In immunosuppressed hosts with a high organism burden, organism death and release of glucans appears to be an important contributor to deleterious host inflammatory responses.

2016-08-31 | GSE79079 | GEO

Super-enhancer-based identification of a BATF3/IL-2R-module reveals vulnerabilities in anaplastic large cell lymphoma [RNA-Seq]

Project description:Systemic anaplastic large cell lymphoma (ALCL) is an aggressive T-cell lymphoma comprising ALK-positive (ALK+) and ALK-negative (ALK−) as well as breast implant-associated (BIA)-ALCL. The prognosis for ALCL, ALK− in particular is poor, and already in second line there is an unmet medical need for effective treatment options. To identify genes defining ALCL cell state and dependencies, we here started by an unbiased characterization of super-enhancer regions by genome-wide H3K27ac chromatin immunoprecipitation sequencing (ChIP-seq). We identified, in addition to known key regulators, the AP-1 transcription factor member BATF3 and IL-2 receptor (IL2R) components among the genes with most extensively H3K27-acetylated regulatory regions. Consistently, specific and high-level expression of the IL-2R subunits, IL-2Rα, IL-2Rβ and IL-2Rγ in ALCL correlate with BATF3 expression. Confirming a regulatory link, expression of IL-2R subunits decreases following BATF3 knockout, and BATF3 is recruited to AP-1 sites in IL2R regulatory regions. Functionally, IL-2, IL-15 and Neo-2/15, a hyper-stable IL-2/IL-15 mimic, accelerate growth of ALCL cells and activate STAT1, STAT5 and ERK, but not STAT3. In line, strong IL-2Rα expression in ALCL patients is linked to more aggressive clinical presentation. Finally, we demonstrate highly efficient killing of ALCL cells by an IL-2Rα-targeting antibody-drug conjugate in vitro and in vivo. Our results highlight the importance of the BATF3/IL-2R module for ALCL biology and identify IL-2Rα as the target of a promising treatment strategy for ALCL.

2021-06-21 | GSE158893 | GEO

Super-enhancer-based identification of a BATF3/IL-2R-module reveals vulnerabilities in anaplastic large cell lymphoma [ChIP-Seq]

2021-06-21 | GSE158915 | GEO

An engineered mycobacterium smegmatis expressing anti-PD-L1/IL-15 immunocytokine induces and activates specific antitumor immunity

Project description:An engineered mycobacterium smegmatis expressing anti-PD-L1/IL-15 immunocytokine induces and activates specific antitumor immunity

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