PD biomarkers for IL-22Fc
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ABSTRACT:
PROVIDER: PRJNA668076 | ENA |
REPOSITORIES: ENA
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Project description:The goal is to identify an IL-22Fc specific gene signature in human intestinal epithelial cells in order to support PD biomarkers for IL-22Fc. We have identified IL-22Fc specific activity in HT-29 cells as secreted acute phase proteins only in the presence of IL-1β. Therefore, HT-29 cells (from gCell) will be cultured with IL-22, IL-1β, IL-6 (as a pSTAT3 activation control) as well as IL-22 + IL-1β and IL-6 + IL-1β. The "SAMID" sample characteristic is a sample identifier internal to Genentech. The ID of this project in Genentech's ExpressionPlot database is PRJ0027983 Keywords: Expression profiling by array
2021-08-11 | GSE159223 | GEO
Project description:Background & Aims: The liver is one of the organs most commonly affected by metastasis. The presence of liver metastasis is reported to be responsible for an immunosuppressive microenvironment and diminished immunotherapy efficacy. Here, we aimed to investigate the role of IL-10 in liver metastasis formation and decipher its therapeutic potential in affecting immunotherapy effectiveness. Methods: To induce spontaneous or forced liver metastasis in mice, murine cancer cells (MC38) or colon tumor organoids were injected into the cecum or the spleen, respectively. Mice with complete and cell-type specific deletion of IL-10- and IL-10Ra were used to identify the source and the target of IL-10 during metastasis formation. Programmed death ligand 1 (PD-L1)-deficient mice were used to test the role of this checkpoint. Flow cytometry was applied to characterize the regulation of IL-10 on PD-L1. Results: We found that Il10-deficient mice and mice treated with IL-10Ra antibodies were protected against liver metastasis formation. Furthermore, by using IL-10 reporter mice, we demonstrated that Foxp3+ regulatory T cells (Tregs) were the major cellular source of IL-10 in liver metastatic sites. Accordingly, deletion of IL-10 in Tregs, but not in myeloid cells, led to reduced liver metastasis. Mechanistically, IL-10 acted on Tregs in an autocrine manner, thereby further amplifying IL-10 production. Furthermore, IL-10 acted on myeloid cells, i.e., monocytes, and induced the upregulation of the immune checkpoint protein PD-L1. Finally, the PD-L1/PD-1 axis attenuated CD8-dependent cytotoxicity against metastatic lesions. Conclusions: Treg-derived IL-10 upregulates PD-L1 expression in monocytes, which in turn reduces CD8+ T-cell infiltration and related antitumor immunity in the context of colorectal cancer (CRC)-derived liver metastasis. These findings provide the basis for future monitoring and targeting of IL-10 in CRC-derived liver metastasis.
2024-02-09 | GSE247304 | GEO
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
Project description:Inhibitory proteins, such as programmed cell death protein 1 (PD-1), have been extensively studied in peripheral T cell responses to foreign, self, and neoantigens. Notably, these proteins are first expressed during T cell development in the thymus. Reports suggest that PD-1 limits regulatory T cell (Treg) development, but the mechanism by which PD-1 exerts this function remains unknown. The present study expands the evaluation of PD-1 and its ligands in the thymus, demonstrating that some of the highest expressers of PD-1 and PD-L1 are agonist selected cells. Surprisingly, we reveal a selective role for PD-1 in regulating the developmental niche only for Tregs as other agonist selected cell populations, such as natural killer T cells, remain unchanged. We also ruled out PD-1 as a regulator of proliferation or cell death of agonist selected Tregs and further demonstrated that PD-1 deficient Tregs have reduced TCR signaling. Unexpectedly, the data suggests that PD-1 deficient thymocytes produce elevated levels of IL-2, a Treg niche limiting cytokine. Collectively, these data suggest a novel role for PD-1 in regulating IL-2 production and the concurrent agonist selection of thymic Tregs. This observation has implications for the use of checkpoint blockade in the context of cancer and infection.
2024-02-19 | GSE255727 | GEO
Project description:In this study we have examined how the cytokine interleukin-2 (IL-2) synergizes with programmed cell death-1 (PD-1) directed immunotherapy during chronic lymphocytic choriomeningitis virus (LCMV) infection. PD-1 blockade in combination with IL-2 is one of the most effective combination therapies in this very stringent LCMV mouse model of life-long chronic infection with irreversible T-cell exhaustion. Our paper makes the following points: First, we show that the more effective viral control seen after PD-1/IL-2 combination therapy compared to PD-1 monotherapy is mediated by the CD8+T-cell response. Then we identify the virus-specific CD8+T cells that proliferate and respond to the combination therapy and show that these are the same lymphoid resident PD-1+TCF-1+stem-like CD8+T cells that act as resource cells to maintain the CD8+T-cell response during chronic infection and also respond to PD-1 blockade. However, the combination therapy dramatically changes the differentiation program of these chronic resource CD8+T cells and results in the generation of transcriptionally and epigenetically distinct effector CD8+T cells that resemble highly functional effector CD8+T cells seen after an acute viral infection. In contrast, PD-1 monotherapy doesnot modify the differentiation program and one gets more virus-specific CD8+T cells but they are transcriptionally and epigenetically similar to what is seen in untreated chronically infected mice. This epigenetic inflexibility of exhausted CD8+T cells is a potential barrier to PD-1 therapy and the ability of this combination therapy to modify the epigenetic signature of virus-specific CD8+T cells during chronic infection could be an important determinant of the striking synergy seen between IL-2 therapy and PD-1 blockade. We also highlight the importance of blocking the PD-1/PD-L1 inhibitory pathway at the target site for effective viral control. Expanding the CD8+ Tcell population and generating better effector cells is important but it is also critical to block PD-1 inhibitory signals at the target site for optimal immunotherapy. Finally, we show that CD25 engagement with IL-2 plays an important and essential role in the observed synergy between IL-2 cytokine and PD-1 blockade. Either blocking CD25 with an antibody or using a mutated version of IL-2 that does not bind CD25 but still binds CD122/132 almost completely abrogated the synergistic effects seen after PD-1/IL-2 combination therapy. There is currently considerable interest in PD-1/IL-2 combination therapy for cancer patients and our fundamental studies defining the underlying mechanisms of how IL-2 synergizes with PD-1 blockade should inform these human translational studies.
2022-06-27 | GSE206732 | GEO
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
Project description:Background: PD-1 immune checkpoint blockade has provided significant clinical efficacy across various types of cancer by unleashing both T- and NK cell-mediated anti-tumor responses. However, resistance to immunotherapy occurs for many patients, rendering the identification of the mechanisms that control PD-1 expression extremely important to increase the response to the therapy Objective: To identify the stimuli and the molecular mechanisms that induce the de novo PD-1 expression on human NK cells in the tumor setting Methods: NK cells freshly isolated from peripheral blood of healthy donors were stimulated with different combinations of molecules, and PD-1 expression was studied at the mRNA and protein level. Moreover, ex vivo analysis of tumor microenvironment and NK cell phenotype was performed. Results: Glucocorticoids (GCs) are indispensable for PD-1 induction on human NK cells, in cooperation with a combination of cytokines that are abundant at the tumor site. Mechanistically, GCs together with IL-12, IL-15 and IL-18 not only upregulate PDCD1 transcription, but also activate a previously unrecognized transcriptional program leading to enhanced mRNA translation and resulting in an increased PD-1 protein amount in NK cells. Conclusion: Our results provide evidence of a novel immune suppressive mechanism of GCs involving the transcriptional and translational control of an important immune checkpoint
2020-04-23 | GSE149113 | GEO
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
Project description:IL-12 has been considered to be an ideal cytokine for cancer immunotherapy as it can activate both immune and adaptive immune systems. However, in clinical trials, severe side effects were observed in patients with IL-12 systemic administrations. In this study, we generated pH-sensitive polymeric micelle encapsulating IL-12 and compared anti-tumor activities of free IL-12, IL-12 micelle and combination of anti-PD-1 and IL-12 micelle.
2023-04-13 | GSE196030 | GEO
Project description:The authors engineer an anti-PD-1-concealed sIL-15 fusion protein (αPD-1-IL-15-R), eliciting extraordinary antitumor immunity with negligible toxicity. αPD-1-IL-15-R largely expands tumor-specific CD8+T for effective tumor rejection through cis-delivery and further controls metastasis.
2022-09-21 | GSE212545 | GEO