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Cytokine gene combination on iPS cell-derived T cells synergistically improves migration, proliferation, and memory formation in solid tumors [ATAC-seq]

ABSTRACT: T cells show anti-tumor efficacy against solid tumor by infiltration, proliferation, and antigen-specific cytotoxicity. In this study, we investigated various combinations of cytokine gene modifications in chimeric antigen receptor-transfected induced pluripotent stem cell-derived T cells (iCAR-T cells). We found that the combination of interleukin 15 (IL-15) and IL-21 gene modification maintained the infiltration and persistence of iCAR-T cells in tumors and significantly prolonged the survival of a subcutaneous tumor-bearing mouse model. As a novel finding, this combination promoted phosphorylation of STAT1 and enhanced the binding of CXCR3 to its promoter region. Furthermore, iCAR-T cells expressing IL-15 and IL-21 were found to have a gene expression profile similar to primary CD8 CAR-T cells in tumors and to have a memory T-cell-like phenotype. Thus, the IL-15 and IL-21 combination may accelerate the therapeutic efficacy of iCAR-T cells for solid tumor immunotherapies as a substitute of peripheral blood CD8 T cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE306476 | GEO | 2026/08/19

REPOSITORIES: GEO

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Cytokine gene combination on iPS cell-derived T cells synergistically improves migration, proliferation, and memory formation in solid tumors

Project description:T cells show anti-tumor efficacy against solid tumor by infiltration, proliferation, and antigen-specific cytotoxicity. In this study, we investigated various combinations of cytokine gene modifications in chimeric antigen receptor-transfected induced pluripotent stem cell-derived T cells (iCAR-T cells). Effective combinations enhanced the anti-tumor efficacy of iCAR-T cells against solid tumors. The combination of interleukin 15 (IL-15) and IL-21 gene modification maintained the infiltration and persistency of iCAR-T cells in tumors and significantly prolonged the survival of a subcutaneous tumor-bearing mouse model. This gene combination was found to enhance the expression of genes related to proliferation, chemotaxis and memory formation. Thus, the IL-15 and IL-21 combination may accelerate the therapeutic efficacy of iCAR-T cells for solid tumor immunotherapies as a substitute of peripheral blood CD8 T cells.

2026-08-19 | GSE252998 | GEO

GPC2-Targeted CAR T Cells Engineered with NFAT-Inducible Membrane-Tethered IL15/IL21 Exhibit Enhanced Activity against Neuroblastoma

Project description:T-cells redirected for antigen-unrestricted cytokine-initiated killing (TRUCKs) are engineered chimeric antigen receptor (CAR) T-cells that constitutively or inducibly release cytokines upon CAR engagement. Their purpose is to enhance the function of effector cells in the immune-suppressive tumor microenvironment (TME) of particularly solid tumors that is often devoid of pro-inflammatory cytokines. We capitalize on the pleiotropic effects of two γc family cytokines, interleukin (IL)-15 and IL-21, and use them synergistically for TRUCK engineering. We demonstrate that TRUCKs with soluble IL-15/IL-21 eradicate CAR T-cell–resistant neuroblastoma, the most common extra-cranial solid tumor of childhood, but are associated with significant toxicities in mice. These toxicities can be delayed when we constitutively tether the cytokines to the surface of T-cells but are abrogated when we engineer CAR T-cells with NFAT-induced membrane-tethered IL-15/IL-21 expression.

2025-06-17 | GSE243349 | GEO

CCL3 and IL-7 Synergistically Enhance CAR-T Efficacy in Solid Tumors

Project description:CAR-T cell therapy has demonstrated remarkable clinical efficacy, but challenges remain in the therapeutic application for solid tumors, primarily due to poor infiltration capacity, suboptimal activity, and tumor antigen escape. Here, we found that the chemokine CCL3 plays a significant role in modulating intratumoral T cell cytotoxicity. However, CCL3 alone is insufficient to sustain durable CAR-T cell mediated tumor killing, largely due to tumor-induced T cell death. In contrast, the combination of CCL3 with IL-7, a cytokine known to enhance T cell survival, exerted a potent synergistic effect. This combination significantly improved CAR-T cell infiltration and longevity in solid tumors, leading to robust anti-tumor efficacy without significant side effects or systemic toxicity. Mechanistically, CCL3 plus IL-7 promoted RUNX3 expression and facilitated the differentiation of CD69+CD103+ tissue-resident memory T (Trm) cells. Furthermore, treatment with CAR-T cells co-expressing CCL3 and IL-7 (3P7-CAR-T) remodeled the immune landscape of solid tumors, marked by an increased infiltration of M1-like macrophages and CD103+ migratory dendritic cells. These changes enhance antigen presentation, thereby promoting the priming of endogenous anti-tumor T cell responses. Taken together, our results demonstrate that CCL3 synergizes with IL-7 to augment CAR-T cell memory and therapeutic effectiveness in solid tumors.

2026-07-15 | GSE330502 | GEO

CCL3 and IL-7 Synergistically Enhance CAR-T Efficacy in Solid Tumors

2026-07-15 | GSE330826 | GEO

Cooperative armoring of CAR and TCR T-cells by T cell-restricted IL-15 and IL-21 universally enhances solid tumor efficacy

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

Spatial transcriptomics data of RM9-hSTEAP1 tumor tissues treated with CAR-T cells

Project description:Immunosuppressive microenvironments, the lack of immune infiltration, and antigen heterogeneity pose challenges for chimeric antigen receptor (CAR)-T cell therapies applied to solid tumors. Previously, CAR-T cells were armored with immunostimulatory molecules, such as interleukin-12 (IL-12), to overcome this issue, but faced high toxicity. Here, we show that collagen-binding domain-fused IL-12 (CBD-IL-12) secreted from CAR-T cells to target human six transmembrane epithelial antigen of the prostate 1 (STEAP1) is retained within murine prostate tumors. This leads to high intratumoral interferon-γ levels, without hepatotoxicity and infiltration of T cells into non-target organs compared with unmodified IL-12. Both innate and adaptive immune compartments are activated and recognize diverse tumor antigens after CBD-IL-12-armored CAR-T cell treatment. Combination of CBD-IL-12-armored CAR-T cells and immune checkpoint inhibitors eradicated large tumors in an established prostate cancer mouse model. Additionally, human CBD-IL-12-armored CAR-T cells showed potent anti-tumor efficacy in an 22Rv1 xenograft while reducing circulating IL-12 levels compared with unmodified IL-12-armored CAR-T cells. CBD-fusion to potent payloads of CAR-T therapy may remove obstacles to their clinical translation towards elimination of solid tumors.

2025-06-25 | GSE300750 | GEO

Human iPSC-derived NK cells armed with CCL19, CCR2B, high-affinity CD16, IL-15, and NKG2D complex enhance anti-solid tumor activity

Project description:Studies of chimeric antigen receptor (CAR)-T and -Natural killer (NK) cells have shown promising results in treating hematological malignancies. However, there are still obstacles to effectively treating solid tumors. These include the challenges of CAR-T cell homing and infiltration, the presence of immunosuppressive microenvironments, and the potential for antigen escape in solid tumors. To overcome the known limitations of immune cell therapy, we engineered human induced pluripotent stem cell (hiPSC)-derived NK (eNK) cells armed with CCL19, CCR2B, high-affinity CD16, IL-15, and NKG2D-DAP10 complex. We introduced the six genes into hiPSCs using the piggyBac system and stimulated them to differentiate into NK cells. Overexpression of NKG2D complex and high-affinity CD16 enhanced the antitumor function of the eNK cells. Overexpression of IL-15 prolonged the persistence of the eNK cells in vitro and in vivo. Forced expression of CCR2B enhanced eNK cell tumor infiltration. Forced expression of CCL19 endowed the eNK cells with the ability to recruit dendritic cells. We found that the eNK cells were able to lyse HLA-E-expressing tumor cells, but not normal human cells. These proof-of-concept studies demonstrate the promise of our eNK cells as a novel adoptive cell therapy product for the treatment of solid tumors.

2025-06-10 | GSE247437 | GEO

Coordinate tumor-antigen uptake and dendritic cell activation by chimeric antigen receptors. [RNA-seq]

Project description:Effective anti-tumor immunity requires dendritic cells (DCs) to internalize, process and present tumor antigens to T cells. Adoptive transfer of DCs loaded ex vivo with tumor antigens has been shown to stimulate anti-tumor immunity in patients with cancer, but clinical responses have been mixed. To address limitations of traditional DC-based therapies, we constructed and functionally screened a panel of chimeric antigen receptors (CARs) optimized for expression and activity in DCs. Through this screening, we identified key functional components that informed the design of an inducible platform centered on an instructive chimeric antigen receptor (iCAR). This platform enables the DCs to (i) recognize a surface molecule present on cancer cells or their extracellular vesicles (EVs), such as GD2 and HER2, thereby promoting the acquisition of tumor-derived material that contains putative tumor antigens; (ii) undergo immunostimulatory activation to prime antigen-specific T cells via both cross-dressing and cross-presentation; and (iii) transactivate the expression of a therapeutic gene (IL-12) in response to antigen uptake. The iCAR converted melanoma-derived EVs from immune-suppressive to stimulatory cues for DCs. Moreover, systemic administration of iCAR-DCs enhanced antigen-specific T cells, expanded low-frequency T cell clonotypes, and delayed tumor growth in immunotherapy-resistant melanoma models without the need for ex vivo antigen loading or cell maturation. iCAR-DCs provide a platform for antigen-agnostic cancer immunotherapy that integrates antigen uptake with programmable DC activation.

2025-12-17 | GSE293372 | GEO

Coordinate tumor-antigen uptake and dendritic cell activation by chimeric antigen receptors. [TCR-seq]

2025-12-17 | GSE293373 | GEO

Trogocytosis contributes tumor escape and limits tumoricidal activity in hPSCs-derived CAR macrophages

Project description:Pluripotent stem cells (PSCs) derived chimeric antigen receptor macrophages (iCAR-Ms) hold great potential for immunotherapy, particularly against T-cell malignancies which are challenging in CAR-T therapy. Here, we generate human iCAR-Ms targeting CD5 for treating T-cell malignancies. iCAR-Ms display tumoricidal activities against various T- malignant cells expressing CD5 such as Jurkat, SUP-T1 and primary tumor cells. However, The iCAR-M tumoricidal activities are largely dependent on CD5 density on tumor cells. The escaped tumor cells show reversible CD5 loss without changes on its mRNA level. Meanwhile, the retrieved iCAR-Ms show little reduced tumoricidal activities against new tumor cells expressing CD5. Based on time lapse imaging and transcriptional analysis, we show that iCAR-Ms mainly medicate trogocytosis while less phagocytosis when approach tumor cells. Our data reveal trogocytosis as an important limitation factor in iCAR-M tumoricidal activities and tumor escape, providing a rational to develop enhanced CAR-M for immunotherapies.

2025-09-01 | GSE305641 | GEO

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