Cooperative armoring of CAR and TCR T-cells by T cell-restricted IL-15 and IL-21 universally enhances solid tumor efficacy
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ABSTRACT:
PROVIDER: PRJNA955221 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24161412.fastq.gz | Fastqsanger.gz | |||
| SRR24161413.fastq.gz | Fastqsanger.gz | |||
| SRR24161414.fastq.gz | Fastqsanger.gz | |||
| SRR24161415.fastq.gz | Fastqsanger.gz | |||
| SRR24161416.fastq.gz | Fastqsanger.gz |
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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:PurposeChimeric 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 universally improve patient outcomes. Here, we developed a technology to leverage the cooperative effects of IL15 and IL21, two common cytokine-receptor gamma chain family members with distinct, pleiotropic effects on T cells and other lymphocytes, to enhance the efficacy of adoptive T cells.Experimental designWe designed vectors that induce the constitutive expression of either membrane-tethered IL15, IL21, or IL15/IL21. We used clinically relevant preclinical models of transgenic CARs and TCRs against pediatric and adult solid tumors to determine the effect of the membrane-tethered cytokines on engineered T cells for human administration.ResultsWe 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 observed enhanced regression with each individual cytokine but the greatest antitumor efficacy when T cells were armored with both.ConclusionsThe coexpression of membrane-tethered IL15 and IL21 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. See related commentary by Ruffin et al., p. 1431.
| S-EPMC11018485 | biostudies-literature
Project description:This SuperSeries is composed of the following subset Series: GSE36520: Identification of a new pathway for Th1 cell development induced by cooperative stimulation with IL-4 and TGFbeta [Affymetrix] GSE36554: Identification of a new pathway for Th1 cell development induced by cooperative stimulation with IL-4 and TGFbeta [Agilent] Refer to individual Series
2012-03-17 | E-GEOD-36556 | biostudies-arrayexpress
Project description:Neoantigens derived from non-synonymous somatic mutations, especially gene fusion mutation, are restricted to tumor cells and thus considered ideal targets for T-cell receptor-engineering T-cells (TCR-T) immunotherapy. Adoptive transfer of neoantigen-specific TCR-T cells preferentially exhibit potent cytotoxicity preferentially to tumor cells, and has shown promising efficacy in several preclinical human cancer models. However, most neoantigens are unique to individual patient, which hinders the application of TCR-T cell therapy. In this study, we first discovered a paired / TCR repertoire, Tcr-1, that specifically targeted STY-SSX fusion neoantigen shared by almost all synovial sarcomas. Engineered T-cell expressing Tcr-1 (Tcr-T1) exhibited antigen-specific HLA-A*2402-restricted antitumoral activity against synovial sarcomas cell both in vitro and in vivo. Furthermore, to furtherly extend its application beyond synovial sarcomas, we innovatively developed a cooperative therapeutic modality, in which exogenous SYT-SSX fusion neoantigen was loaded into enzyme-responsive nanoparticles (NPs) formed by mPEG-PVGLIG-PCL copolymers (FNeo-AgNPs) for tumor targeting delivery. As expected, FNeo-AgNPs were proven of great tumor penetration, and local release. In situ modification was able to direct engineered Tcr-T1 against to other malignant gastric cancer cell line with significant antigen-specific HLA-A*2402-restricted cytotoxicity resulting in remarkable tumor regression and prolonging survival in both subcutaneous and peritoneally disseminated preclinical models, despite of their inherent mutation profiles. With these favorable data, our established cooperative therapeutic modality has a great potential for further clinical investigation, and provide a now insight for future TCR-T cell therapy development.
2024-11-18 | GSE243535 | GEO
Project description:Interleukin-10 (IL-10) is a pleiotropic anti-inflammatory cytokine produced and sensed by most hematopoietic cells. Genome wide association studies and experimental animal models point at a central role of the IL-10 axis in Inflammatory Bowel Diseases. Here we investigated the importance of intestinal macrophage production of IL-10 and their IL-10 exposure, as well as the existence of an IL-10-based autocrine regulatory loop in the gut. Specifically, we generated mice harboring IL-10 or IL-10 receptor (IL-10R?) mutations in intestinal lamina propria-resident chemokine receptor CX3CR1hi-expressingmacrophages. We found macrophage-derived IL-10 dispensable for gut homeostasis and maintenance of colonic T regulatory cells. In contrast, loss of IL-10 receptor expression impaired the critical conditioning of these monocyte-derived macrophages, but resulted in spontaneous development of severe colitis. Collectively, our results highlight IL-10 as a critical homeostatic macrophage-conditioning factor in the colon and define intestinal CX3CR1hi macrophages as a decisive factor that determines gut health or inflammation. Microarray of resident macrophages sorted from colons of Interleukin-10 deficeint mice and macrophage-restricted interleukin-10 receptor deficient mice versus colonic resident macrophages of wild type mice
2014-05-09 | E-GEOD-56444 | biostudies-arrayexpress
Project description:The common gamma chain (γc) is required for productive signaling by interleukin (IL)-15, IL-21 and IL-2, which are critically involved in immune activation and regulation. IL-21 and IL-15 are implicated in the pathogenesis of type-1 diabetes, graft-versus-host disease, and celiac disease (CeD), a gluten-mediated autoimmune-like enteropathy. Attempts to treat type-1 diabetes and graft-versus-host disease with biologics targeting one particular cytokine have failed. Both IL-15 and IL-21 have been suggested to drive activation of cytotoxic T cells (CTL) that are the effectors mediating tissue destruction in CeD and organ-specific autoimmune disorders. We show that the concomitant upregulation of IL-15 and IL-21 occurs only in full-blown CeD with villous atrophy. BNZ-2, a peptide that targets the γc, was able to block the cooperative IL-15/IL-21 mediated transcriptional activation of human tissue-resident intraepithelial CTL. Importantly, this inhibition was specific and did not interfere with IL-2 signaling, a cytokine with known immunoregulatory functions. Moreover, BNZ-2 blocked gluten-induced IFN-γ production in small intestinal organ cultures from CeD patients. These observations identify BNZ-2 as a therapeutic candidate for immune disorders in which IL-15 and IL-21 cooperate to induce CTL-mediated tissue damage.
2018-10-06 | GSE120904 | GEO
Project description:IL-4 is classically associated with “M2” macrophages considered tumor-immunosuppressive, yet marker-based labels poorly reflect macrophage function in tumors. Reports of a non-canonical, IL-4–imprinted macrophage state (M2inf) with trained-immunity features prompted us to test whether such imprinting contributes to antitumor immunity in vivo. Here we show that, in B16F10 melanoma, IL-4 programs macrophages through the lysine methyltransferase Smyd5 to deposit promoter-proximal H3K36me3, increase MHC class II, and potentiate T cell activation. Myeloid Il4ra deletion increased tumor burden and reduced MHC class II and intratumoral T cell activation, whereas co-transfer of IL-4–primed macrophages suppressed tumors and expanded activated CD4 and CD8 T cells. Antitumor benefit required adaptive lymphocytes and macrophage-intrinsic MHC class II, as Rag1 deficiency or macrophage Rfx5 deletion abrogated tumor suppression. These findings identify a non-canonical, IL-4–imprinted macrophage program that enables antigen presentation and cooperative T cell immunity in this tumor context.
2026-01-26 | GSE315363 | GEO
Project description:IL-4 is classically associated with “M2” macrophages considered tumor-immunosuppressive, yet marker-based labels poorly reflect macrophage function in tumors. Reports of a non-canonical, IL-4–imprinted macrophage state (M2inf) with trained-immunity features prompted us to test whether such imprinting contributes to antitumor immunity in vivo. Here we show that, in B16F10 melanoma, IL-4 programs macrophages through the lysine methyltransferase Smyd5 to deposit promoter-proximal H3K36me3, increase MHC class II, and potentiate T cell activation. Myeloid Il4ra deletion increased tumor burden and reduced MHC class II and intratumoral T cell activation, whereas co-transfer of IL-4–primed macrophages suppressed tumors and expanded activated CD4 and CD8 T cells. Antitumor benefit required adaptive lymphocytes and macrophage-intrinsic MHC class II, as Rag1 deficiency or macrophage Rfx5 deletion abrogated tumor suppression. These findings identify a non-canonical, IL-4–imprinted macrophage program that enables antigen presentation and cooperative T cell immunity in this tumor context.
2026-01-26 | GSE315361 | GEO
Project description:IL-4 is classically associated with “M2” macrophages considered tumor-immunosuppressive, yet marker-based labels poorly reflect macrophage function in tumors. Reports of a non-canonical, IL-4–imprinted macrophage state (M2inf) with trained-immunity features prompted us to test whether such imprinting contributes to antitumor immunity in vivo. Here we show that, in B16F10 melanoma, IL-4 programs macrophages through the lysine methyltransferase Smyd5 to deposit promoter-proximal H3K36me3, increase MHC class II, and potentiate T cell activation. Myeloid Il4ra deletion increased tumor burden and reduced MHC class II and intratumoral T cell activation, whereas co-transfer of IL-4–primed macrophages suppressed tumors and expanded activated CD4 and CD8 T cells. Antitumor benefit required adaptive lymphocytes and macrophage-intrinsic MHC class II, as Rag1 deficiency or macrophage Rfx5 deletion abrogated tumor suppression. These findings identify a non-canonical, IL-4–imprinted macrophage program that enables antigen presentation and cooperative T cell immunity in this tumor context.
2026-01-26 | GSE315255 | GEO
Project description:IL-4 is classically associated with “M2” macrophages considered tumor-immunosuppressive, yet marker-based labels poorly reflect macrophage function in tumors. Reports of a non-canonical, IL-4–imprinted macrophage state (M2inf) with trained-immunity features prompted us to test whether such imprinting contributes to antitumor immunity in vivo. Here we show that, in B16F10 melanoma, IL-4 programs macrophages through the lysine methyltransferase Smyd5 to deposit promoter-proximal H3K36me3, increase MHC class II, and potentiate T cell activation. Myeloid Il4ra deletion increased tumor burden and reduced MHC class II and intratumoral T cell activation, whereas co-transfer of IL-4–primed macrophages suppressed tumors and expanded activated CD4 and CD8 T cells. Antitumor benefit required adaptive lymphocytes and macrophage-intrinsic MHC class II, as Rag1 deficiency or macrophage Rfx5 deletion abrogated tumor suppression. These findings identify a non-canonical, IL-4–imprinted macrophage program that enables antigen presentation and cooperative T cell immunity in this tumor context.
2026-01-26 | GSE315253 | GEO