Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

PD1-targeted cis-delivery of an IL-2 variant induces a multifaceted anti-tumoral T cell response in human lung cancer

ABSTRACT: Antibody-cytokine fusion proteins are being developed as next-generation cancer immunotherapies, aiming to deliver activation signals to targeted immune populations. Among these, PD1-IL2v - an engineered interleukin-2 variant (IL-2v) lacking CD25 binding, fused to a high affinity programmed cell death protein-1 (PD-1) blocking antibody - has shown promising results in murine tumor models. Here, using human model systems, we show that PD1-IL2v elicits a multifaceted anti-tumor T cell response by targeting both CD8⁺ and conventional CD4⁺ T cells (Tconv). Single cell RNA sequencing (scRNAseq) on a lung cancer patient-derived tumor fragment (PDTF) platform revealed that PD1-IL2v drives the expansion of proliferative, cytotoxic CD8⁺ T cells exhibiting features of tumor reactivity. This was accompanied by upregulation of CXCR6, enhancing their migratory capacity. In Tconv cells, PD1-IL2v upregulated CXCL13 expression and promoted a Tfh/Th1-like transcriptional program associated with anti-PD1 responsiveness. Our findings provide mechanistic insights into the effects of IL-2v targeted delivery to PD-1⁺ cells within human tumors, supporting the clinical development of next-generation immunocytokines.

ORGANISM(S): Homo sapiens

PROVIDER: GSE303680 | GEO | 2025/07/30

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

The immunocytokine PD1-IL2v overcomes resistance to tumor immunity, and synergizes with anti-PD-L1

Project description:Immunotherapies have shown remarkable, albeit tumor-selective therapeutic benefits in the clinic. Here we evaluated the effects of the immunocytokine PD1-IL2v in a mouse model of de novo pancreatic neuroendocrine cancer resistant to checkpoint and other immunotherapies. PD1-IL2v is a bi-specific molecule based on a bivalent PD-1 antibody, serving as a targeting moiety, fused to an immuno-stimulatory IL-2 variant (IL2v) to precisely deliver IL2v to PD-1+ T-cells in the tumor microenvironment. PD1-IL2v elicited dramatic infiltration by CD8 T cells, notably stem-like and effector memory T cells, resulting in tumor regression and enhanced survival in mice. Furthermore, combining anti-PD-L1 with PD1-IL2v sustained the response phase, improving therapeutic efficacy both by reprogramming immunosuppressive tumor-associated macrophages and tumor endothelial cells , and by enhancing TCR immune repertoire diversity. The data motivate consideration of clinical trials to evaluate the combination therapy of PD1-IL2v and anti-PD-L1, especially in immunotherapy-resistant tumors infiltrated with PD-1+ T stem-like CD8 T cells.

2023-01-10 | GSE197854 | GEO

An Engineered IL-15 Cytokine Mutein Fused to an Anti-PD1 Antibody Improves Intratumoral T Cell Function and Anti-tumor Immunity (human)

Project description:Background: Cancer Immunotherapy with cytokines has demonstrated clinical efficacy but is frequently accompanied with severe adverse events caused by excessive and systemic immune activation. Here, we addressed these challenges by engineering a fusion protein of a single, potency-reduced, IL-15 mutein and an anti-PD1 antibody (αPD1-IL15m). This immunocytokine is designed to deliver PD1-mediated avidity-driven IL-2/15 receptor stimulation preferentially to PD1-positive tumor-infiltrating lymphocytes (TILs) while reducing the natural preference of IL-15 for circulating peripheral NK or T cell Methods: We isolated human lymphocytes from resected hepatocellular carcinoma tissue and cultured these tumor-infiltrating lymphocytes (TILs) in vitro in the presence or absence of an PD1-targeted IL15 mutein, anti-PD1 antibody or IL-15 agonist. After 9 days, CD4+ TILs and CD8+ TILs were sorted by FACS and RNA of 3,000 to 150,000 cells was isolated. Results: The PD1-IL15 fusion cytokine enhanced pro-survival, proliferation and activation pathways in tumor-infiltrating CD4+ and CD8+ cells compared to untreated controls as well as to the combined treatment of single agents (anti-PD1 antibody and IL-15 agonist)

2021-05-25 | GSE157893 | GEO

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

An Engineered IL-15 Cytokine Mutein Fused to an Anti-PD-1 Antibody Improves Intratumoral T Cell Function and Anti-tumor Immunity

Project description:The anti-PD-1 antibody-IL-15 cytokine fusion approach was developed to optimally activate intra-tumoral CD8+ T cells. We engineered a fusion protein of a single, potency-reduced, IL-15 mutein and an anti-PD-1 antibody (αPD1-IL15m). This immunocytokine is designed to deliver PD-1-mediated avidity-driven IL-2/15 receptor stimulation preferentially to PD-1-positive tumor-infiltrating lymphocytes (TILs) while reducing the natural preference of IL-15 for circulating peripheral NK or T cells.

2021-07-13 | GSE160579 | GEO

PD-1+TCF-1+ stem-like CD8 T cells differentiate into effector T cells with enhanced anti-tumor and viral efficacy upon PD-1 cis-targeted IL-2R-agonism”

Project description:Here we show that IL-2Rbg-biased agonists are unable to preferentially expand better effector T cells in cancer models, and describe PD1-IL2v, a novel immunocytokine, that overcomes the need for CD25 binding by docking in cis to PD-1. In cis binding of PD1-IL2v to PD-1 and IL-2Rbg on the same cell recovers the ability to differentiate stem-like CD8 T cells into better effectors in the absence of CD25 binding in both chronic infection and cancer models, and provides superior efficacy.

2022-07-21 | GSE208556 | GEO

Targeting IL-21 to tumor-reactive T cells enhances memory T cell responses and anti-PD-1 antibody therapy

Project description:T cell rejuvenation by PD-1/PD-L1 blockade, despite emerging as a highly promising therapy for advanced cancers, is only beneficial for a minority of treated patients. There is evidence that a lack of efficient T cell activation may be responsible for the failure. Here, we demonstrate that IL-21 can be targeted to tumor-reactive T cells by fusion of IL-21 to anti-PD-1 antibody. To our surprise, the fusion protein PD-1Ab21 promoted the generation of TSCM-like CD8+ T cells with enhanced cell proliferation. A transcriptome analysis of isolated TN, activated and PD-1Ab-cultured CD44highCD62Lhigh T cells, IL-2-generated TE/TEM, IL-15-generated TCM as well as PD-1Ab21 and IL-21-generated CD44lowCD62Lhigh T cells provides corroborating evidence that PD-1Ab21 induces conversion of activated CD8+ T cells back to a memory subset that is distinct from TCM cells, but similar to TSCM. PD-1Ab21 treatment showed potent antitumor effects in established tumor-bearing mice accompanied with an increased frequency of TSCM and robust expansion of tumor-specific CD8+ T cells with a memory phenotype, and was superior to a combination of PD-1 blockade and IL-21 infusion. Therefore, we have developed a potential strategy to improve the therapeutic effects of immune checkpoint blockade by simultaneously targeting cytokines to tumor-reactive T cells.

2021-01-01 | GSE164093 | GEO

Crosslinking of Ly6a metabolically reprogram CD8 T cells for cancer immunotherapy.

Project description:To evaluate the downstream effects of anti-Ly6a crosslinking, we examined the effect of anti-Ly6a antibodies on CD8+ T cell activity in the presence and absence of target tumor cells by high-resolution mass spectrometry proteomic analyses. Spleen cells were isolated from gp10025–33 TCR transgenic mice and incubated for 3 days with IL-2, IFNα, and gp10025–33 peptide. Next, CD8+ T-cells were isolated and incubated overnight with anti-Ly6a antibody (or IgG with or without B16F10 melanoma cells. CD8+ T-cells were then sorted and subjected to proteomic analysis using high-resolution mass spectrometry

2024-08-04 | PXD050734 | Pride

Attenuated IL-2 Signaling Rewires Transcriptional and Metabolic Programs in T Cells to Enable Coupling Proliferation and Stemness

Project description:Interleukin-2 (IL-2) is a fundamental cytokine that controls the proliferation and differentiation of T cells1. Its direct administration in vivo has conferred durable, complete responses in patients with metastatic melanoma and renal cell cancer, while it is also used to expand tumor-infiltrating lymphocytes (TILs) in vitro for adoptive cell therapy (ACT)2. Unfavorable properties of IL-2 including terminal differentiation of effector T cells3-6, induction of activation-induced cell death (AICD)2, 7, 8, expansion of regulatory T (Treg) cells, and toxicity at high doses, have driven the development of IL-2 variants with modified biological properties9-13. However, how cytokine modifications alter cell fate decisions is not well understood. Here, taking a systems biology approach we have comprehensively elucidated how a non CD25-binding, IL-2-biased agonist (IL-2v)14 reprograms signaling, transcriptional, and metabolic networks of CD8+ T cells in vitro to favor stemness while simultaneously driving expansion and functionality. Such "expansion-stemness state" defines metabolically fit CD8+ T cells capable of superior persistence and tumor control. These findings broaden our fundamental understanding of the effects of IL-2v on T-cell biology and provide an investigational framework for the rational development and evaluation of cytokine variants with clinical relevance.

2025-01-01 | GSE223651 | GEO

Transcriptional characterization of PD-1 positive and negative Foxp3 negative CD4 positive T cells from liver of 5- and 10-day-old Aire-deficient C57BL/6 mice

Project description:The first T cells to arrive in the liver were mostly T regulatory (Treg) cells and metabolically active, highly proliferative T conventional (Tconv) cells. The Tconv cells had unusually high expression of PD-1 and the IL-33 receptor, ST2. As these PD-1+ Tconv cells accumulated in the tissue, they gradually lost their expression of ST2, ceased to proliferate and acquired an anergic phenotype.

2019-03-28 | GSE127882 | GEO

Transcriptional profiling of IL6R-deficient CD8 T cells isolated from subcutaneous MC38 tumors treated with anti-PD-L1 therapy

Project description:Interleukin 6 (IL-6) is a pleiotropic cytokine with diverse roles in homeostasis, inflammation, and cancer. In multiple syngeneic mouse tumor models, we found that blockade of IL-6 signaling (using an IL6R-blocking antibody) synergized with anti-PD-L1 therapy to drive potent anti-tumor CD8 T cell responses and tumor rejection. To better characterize the cell-intrinsic effects of IL-6 signaling in tumor-reactive CD8+ T cells during anti-PD-L1 therapy, we generated mice with genetic IL6R deficiency restricted to CD8 T cells by crossing IL6R.loxp and E8i.CD8.Cre mice (CD8ΔIL6R mice). Compared to WT littermate controls, we found that CD8ΔIL6R mice had stronger respones to anti-PD-L1 therapy in terms of improved CD8 T cell function (e.g. increased production of IFNγ and TNF, measured by flow cytometry) and enhanced tumor control, suggesting that direct IL-6 signaling in CD8 T cells is sufficient to impair anti-tumor immunity. In this study we aimed to characterize the phenotype of IL6R-deficient CD8 T cells in more detail via whole-transcriptome profiling. CD8ΔIL6R and WT littermates were implanted with MC38 tumors in the right flank; when tumors reached ~150mm3 in volume, animals were randomized to isotype control or anti-PD-L1 treatment. CD8 T cells were FACS-purified from tumor tissue 7 days later and profiled by bulk RNAseq. Compared to cells from WT mice, CD8 T cells from CD8ΔIL6R mice showed increased expression of interferon-driven gene signatures, increased expression of cell cycle genes, and increased expression of genes critical for oxidative phosphorylation. In contrast, WT cells had higher expression of genes associated with naive and memory precursor cells. Thus, IL-6 signaling in tumor-reactive CD8 T cells limits their capacity to differentiate into potent anti-tumor effectors.

2022-11-04 | GSE199047 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data