Synthetic IL-21 cytokine mimetic promotes T cell function
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE240834 | GEO | 2025/06/18
REPOSITORIES: GEO
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Project description:Synthetic IL-21 cytokine mimetic promotes T cell function
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Project description:Cell therapy with tumor-infiltrating lymphocytes (TIL) has yielded durable responses for multiple cancer types, but the causes of therapeutic resistance remain largely unknown. Here multi-dimensional analysis was performed on time serial tumor and blood in a lung cancer TIL therapy trial. Using T-cell receptor sequencing on both functionally expanded T cells and neoantigen-loaded tetramer-sorted T cells, we identified neoantigen specific TCRs. We then mapped clones into individual transcriptomes and found that neoantigen-reactive clonotypes expressed a dysfunctional program and lacked stem-like features among patients who lacked clinical benefit. Tracking neoantigen-reactive clonotypes over time, decay of antigen-reactive peripheral T-cell clonotypes was associated with the emergence of progressive disease. Further, subclonal neoantigens previously targeted by infused T cells were subsequently absent within tumors at progression, suggesting potential adaptive resistance. Our findings suggest that targeting clonal antigens and circumventing dysfunctional states may be important for conferring clinical responses to TIL therapy.
2024-12-30 | PXD049438 | Pride
Project description:Chimeric antigen receptor (CAR) and T-cell receptor (TCR) T-cell therapies are effective in a subset of patients with solid tumors, but new approaches are needed to enhance efficacy and universally improve patient outcomes. IL-15 and IL-21 are common cytokine-receptor gamma chain family members with distinct, pleiotropic effects on T-cells and other lymphocytes. We found that self-delivery of these cytokines by CAR or TCR T-cells prevents functional exhaustion by repeated stimulation and limits the emergence of dysfunctional natural killer (NK)-like T-cells. Across different preclinical murine solid tumor models, we observe enhanced regression with each individual cytokine but the greatest anti-tumor efficacy when T-cells are armored with both. Thus, the co-expression of membrane-tethered IL-15 and IL-21 represents a technology to enhance the resilience and function of engineered T-cells against solid tumors and could be applicable to multiple therapy platforms and diseases.
2023-08-29 | GSE229651 | GEO
Project description:Recombinant cytokines were the first modern immunotherapies to produce durable cures in metastatic cancer, but their application has been hampered by only modest efficacy and limited tolerability. Next-generation cytokine therapies are therefore under development to overcome the biological limitations of native cytokines. By analyzing single-cell transcriptomic data from tumor infiltrating lymphocytes (TIL), we found that components of the Interleukin-18 (IL-18) pathway are upregulated on activated and dysfunctional TIL, suggesting that IL-18 therapy could potentially restore anti-tumor immunity by stimulating these key effector cells. However, recombinant IL-18 therapy has consistently failed to demonstrate anti-tumor efficacy in clinical trials. Here we show that the secreted, high-affinity decoy receptor IL-18BP is frequently upregulated in the tumor microenvironment of diverse human cancers and syngeneic murine tumor models. Using directed evolution, we engineered a ‘decoy-resistant’ IL-18 (DR-18), which maintains signaling potential, but is impervious to binding and inhibition by IL-18BP. In contrast to wild-type IL-18, DR-18 exhibits potent anti-tumor efficacy as monotherapy and in combination with anti-PD-1 checkpoint immunotherapy in multiple tumor models. Mechanistically, DR-18 drives the development of poly-functional effector CD8+ T cells, decreases the prevalence of exhausted CD8+ T cells expressing the transcription factor TOX, and expands the pool of TCF1+ precursor CD8+ T cells. DR-18 also enhances NK cell activity and maturation to effectively treat anti-PD-1 resistant tumors that have lost MHC class I surface expression. Together, these results highlight the IL-18 pathway as a powerful target for immunotherapeutic intervention and implicate the secreted immune checkpoint IL-18BP as an obstacle to effective IL-18 immunotherapy.
2020-06-29 | GSE146609 | GEO
Project description:In our study, we have characterized the non-expanded and expanded tumor-infiltrating lymphocytes (TILs) from treatment-naive renal cell carcinoma (RCC) patients (n=3), as well as the minimally cultured pre-REP TILs and rapidly expanded REP TILs with a clinical-grade TIL expansion protocol. We observed that the REP TILs encompassed an abundance of CD4positive T-cells, together with increased LAG-3 and low PD-1 expression in the CD4positive and CD8positive T-cells. In addition, we observed that the TIL expansion protocol expanded small CD4positive T-cell clonotypes in the tumor microenvironment (TME), and that the large, exhausted tumor T-cell clonotypes do not expand. We further identified RCC-associated TCR motifs that were validated in multiple TCRalpha-beta-seq and scRNAand TCRalpha-beta-seq datasets, as well as quantified the RCC-associated TCRs from the REP protocol. Overall, the T-cells carrying the RCC-associated TCRs remained high in the tumors and corresponding pre-REP TILs, but the frequency was reduced in the REP TILs. Furthermore, the overall anti-viral TCRs remained low throughout the REP protocol. Our results provide an in-depth understanding of the origin, immunophenotype, and specificity of the TCRs in RCC TILs.
2023-12-29 | E-MTAB-12910 | biostudies-arrayexpress
Project description:IL-2 and IL-21 are closely related cytokines that might have arisen by gene duplication. Both cytokines promote the function of effector CD8+ T cells, but their distinct effects on antigen-driven differentiation of naïve CD8+ T cells into effector CD8+ T cells are not clearly understood. We found that antigen-induced expression of eomesodermin and maturation of naïve CD8+ T cells into granzyme B and CD44 expressing effector CD8+ T cells was enhanced by IL-2, but, unexpectedly, suppressed by IL-21. Furthermore, IL-21 repressed expression of IL-2Ra and inhibited IL-2-mediated acquisition of a cytolytic CD8+ T cell phenotype. Despite its inhibitory effects, IL-21 did not induce anergy, but instead potently enhanced the capacity of cells to mediate tumor regression upon adoptive transfer. In contrast, IL-2, surprisingly, impaired the subsequent anti-tumor function of transferred cells. Gene expression studies revealed a distinct IL-21-program that was characterized phenotypically by increased expression of L-selectin and functionally by enhanced anti-tumor immunity that was not reversed by secondary in vitro stimulation with antigen and IL-2. Thus, the efficacy of CD8+ T cells for adoptive immunotherapy can be influenced by opposing differentiation programs conferred by IL-2 and IL-21, a finding with important implications for the development of cellular cancer therapies. Two-condition experiment: Cytokine-exposed t-cells subsequentially restimulated without cytokine vs. control t-cells without cytokine subsquentially restimulated without cytokine. 3 independent experiments - 1 with experimental RNA labeled with Cy5, control with Cy3, and 2 with dyes-swapped Keywords: Cytokine exposure comparison Comparitive analysis of cytokine effects on lymphocyte gene expression. GSM265712.gpr (S89_1_IL2_0.gpr): Cy3 - control, Cy5 - experimental GSM265713.gpr (S90_1_IL15_0.gpr): Cy3 - control, Cy5 - experimental GSM265714.gpr (S91_1_IL21_0.gpr): Cy3 - control, Cy5 - experimental GSM265715.gpr (S27_2_0_IL2.gpr): Cy3 - experimental, Cy5 - control GSM265716.gpr (S29_2_0_IL15.gpr): Cy3 - experimental, Cy5 - control GSM265717.gpr (S30_2_0_IL21.gpr): Cy3 - experimental, Cy5 - control GSM265718.gpr (S31_3_0_IL2.gpr): Cy3 - experimental, Cy5 - control GSM265719.gpr (S33_3_0_IL15.gpr): Cy3 - experimental, Cy5 - control
2010-05-26 | E-GEOD-10403 | biostudies-arrayexpress
Project description:Adoptive T cell transfer (ACT) is a promising approach to cancer immunotherapy, but its efficiency fundamentally depends on the extent of tumor-specific T-cell enrichment within the graft. This can be estimated via activation with identifiable neoantigens, tumor-associated antigens (TAAs), or living or lyzed tumor cells, but these approaches remain laborious, time-consuming, and functionally limited, hampering clinical development of ACT. Here, we demonstrate that homology cluster analysis of T cell receptor (TCR) repertoires efficiently identifies tumor-reactive TCRs allowing to: 1) detect their presence within the pool of tumor-infiltrating lymphocytes (TILs); 2) optimize TIL culturing conditions, with IL-2low/IL-21/anti-PD-1 combination showing increased efficiency; 3) investigate surface marker-based enrichment for tumor-targeting T cells in freshlyisolated TILs (enrichment confirmed for CD4+ and CD8+ PD-1+/CD39+ subsets), or re-stimulated TILs (informs on enrichment in 4-1BB-sorted cells). We believe that our approach to the rapid assessment of tumor-specific TCR enrichment should accelerate T cell therapy development.
2024-02-14 | GSE197003 | GEO
Project description:Small-molecule Smac mimetics target inhibitor of apoptosis (IAP) proteins to induce TNFα-dependent apoptosis in cancer cells and several Smac mimetics have been advanced into clinical development as a new class of anticancer drugs. However, preclinical studies have shown that only a small subset of cancer cell lines are sensitive to Smac mimetics used as single agents and these cell lines are at risk of developing drug resistance to Smac mimetics. Thus, it is important to understand the molecular mechanisms underlying intrinsic and acquired resistance of cancer cells to Smac mimetics in order to develop effective therapeutic strategies to overcome or prevent Smac mimetic resistance. We established Smac mimetic resistant sublines derived from MDA-MB-231 breast cancer cells, which exhibit exquisite sensitivity to the Smac mimetic SM-164, and used microarrays to detail the global programme of gene expression underlying SM-164 resistance in MDA-MB-231 cells and identified differentially expressed genes in SM-164-resistant and -sensitive MDA-MB-231 cells. SCID mice with MDA-MB-231 xenograft tumors were treated with 5 mg/kg of SM-164 intravenously for 5 days/week for 2 weeks. SM-164-regressed MDA-MB-231 tumors regrew after treatment ended. Tumor cells from these regrown MDA-MB-231 tumors were isolated and total RNAs were prepared for microarray analysis.
2012-03-01 | E-GEOD-33827 | biostudies-arrayexpress
Project description:IL-2 and IL-21 are closely related cytokines that might have arisen by gene duplication. Both cytokines promote the function of effector CD8+ T cells, but their distinct effects on antigen-driven differentiation of naïve CD8+ T cells into effector CD8+ T cells are not clearly understood. We found that antigen-induced expression of eomesodermin and maturation of naïve CD8+ T cells into granzyme B and CD44 expressing effector CD8+ T cells was enhanced by IL-2, but, unexpectedly, suppressed by IL-21. Furthermore, IL-21 repressed expression of IL-2Ra and inhibited IL-2-mediated acquisition of a cytolytic CD8+ T cell phenotype. Despite its inhibitory effects, IL-21 did not induce anergy, but instead potently enhanced the capacity of cells to mediate tumor regression upon adoptive transfer. In contrast, IL-2, surprisingly, impaired the subsequent anti-tumor function of transferred cells. Gene expression studies revealed a distinct IL-21-program that was characterized phenotypically by increased expression of L-selectin and functionally by enhanced anti-tumor immunity that was not reversed by secondary in vitro stimulation with antigen and IL-2. Thus, the efficacy of CD8+ T cells for adoptive immunotherapy can be influenced by opposing differentiation programs conferred by IL-2 and IL-21, a finding with important implications for the development of cellular cancer therapies. Two-condition experiment: Cytokine-exposed t-cells subsequentially restimulated without cytokine vs. control t-cells without cytokine subsquentially restimulated without cytokine. 3 independent experiments - 1 with experimental RNA labeled with Cy5, control with Cy3, and 2 with dyes-swapped Keywords: Cytokine exposure comparison
2008-02-13 | GSE10403 | GEO
Project description:Cell therapy with tumor-infiltrating lymphocytes (TIL) has yielded durable responses for multiple cancer types, but the causes of therapeutic resistance remain largely unknown. Here multi-dimensional analysis was performed on time serial tumor and blood in a lung cancer TIL therapy trial. Using T-cell receptor sequencing on both functionally expanded T cells and neoantigen-loaded tetramer-sorted T cells, we identified tumor antigen specific TCRs. We then mapped clones into individual transcriptomes and found that tumor-reactive clonotypes expressed a dysfunctional program and lacked stem-like features among patients who lacked clinical benefit. Tracking tumor-reactive clonotypes over time, decay of antigen-reactive peripheral T-cell clonotypes was associated with the emergence of progressive disease. Further, subclonal neoantigens previously targeted by infused T cells were subsequently absent within tumors at progression, suggesting potential adaptive resistance. Our findings suggest that targeting clonal antigens and circumventing dysfunctional states may be important for conferring clinical responses to TIL therapy.
2025-03-12 | GSE291406 | GEO