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Radiopharmaceuticals enhance CAR T-cells against radio-sensitive and radio-resistant neuroblastoma by tumor sensitization and TME remodeling [scRNA-Seq]

ABSTRACT: Chimeric antigen receptor (CAR) T-cell therapy has limited efficacy against solid tumors such as neuroblastoma (NB). Key obstacles include extensive tumor burden and the presence of an immunosuppressive tumor microenvironment (TME). We employ targeted radiopharmaceutical therapy (RPT) using [67Cu]Cu-LLP2A and find that it potentiated the anti-tumor activity of CAR T-cells in radio-sensitive and radio-resistant NB models via distinct mechanisms. In radio-sensitive NB, RPT is directly tumoricidal while also enhancing CAR T-cell efficacy through pro-immune pathways, most notably via the TNFα pathway, leading to paracrine activation of T-cells. In radio-resistant NB, RPT improves CAR T-cells by remodeling the myeloid compartment in the TME and increasing the formation of immunological niches of cytotoxic CD8⁺ GZMB⁺ and CD4⁺ GZMB+ CAR T-cells. While neither treatment modality alone can effectively treat NB, the combination of VLA-4-targeted RPT and GD2 or B7-H3 CAR T-cells augments anti-tumor efficacy, resulting in marked tumor regression in preclinical NB models.

ORGANISM(S): Homo sapiens

PROVIDER: GSE330930 | GEO | 2026/05/18

REPOSITORIES: GEO

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Radiopharmaceuticals enhance CAR T-cells against radio-sensitive and radio-resistant neuroblastoma by tumor sensitization and TME remodeling [RNA-Seq]

Project description:Chimeric antigen receptor (CAR) T-cell therapy has limited efficacy against solid tumors such as neuroblastoma (NB). Key obstacles include extensive tumor burden and the presence of an immunosuppressive tumor microenvironment (TME). We employ targeted radiopharmaceutical therapy (RPT) using [67Cu]Cu-LLP2A and find that it potentiated the anti-tumor activity of CAR T-cells in radio-sensitive and radio-resistant NB models via distinct mechanisms. In radio-sensitive NB, RPT is directly tumoricidal while also enhancing CAR T-cell efficacy through pro-immune pathways, most notably via the TNFα pathway, leading to paracrine activation of T-cells. In radio-resistant NB, RPT improves CAR T-cells by remodeling the myeloid compartment in the TME and increasing the formation of immunological niches of cytotoxic CD8⁺ GZMB⁺ and CD4⁺ GZMB+ CAR T-cells. While neither treatment modality alone can effectively treat NB, the combination of VLA-4-targeted RPT and GD2 or B7-H3 CAR T-cells augments anti-tumor efficacy, resulting in marked tumor regression in preclinical NB models.

2026-05-18 | GSE330929 | GEO

Preclinical optimization of a GPC2-targeting CAR T cell therapy for neuroblastoma

Project description:Background: Although most patients with newly diagnosed high-risk neuroblastoma (NB) achieve remission after initial therapy, more than 50% experience late relapses caused by minimal residual disease (MRD) and succumb to their cancer. Therapy strategies to target MRD may benefit these children. We developed a new chimeric antigen receptor (CAR) targeting glypican (GPC)2 and conducted iterative preclinical engineering of the CAR structure to maximize its anti-tumor efficacy before clinical translation. Methods: We evaluated different GPC2-CAR constructs by measuring the CAR activity against several NB cell lines in vitro. NOD-SCID mice engrafted with human NB cell lines or orthotopic patient-derived xenograft (PDX) and treated with human CAR T cells served as in vivo models. Mechanistic studies were performed using single-cell RNA-sequencing. Results: Applying stringent in vitro assays and orthotopic in vivo NB models, we demonstrated that our single-chain variable fragment, CT3, integrated into a CAR backbone with a CD28 hinge, CD28 transmembrane, and 4-1BB co-stimulatory domain elicits the best preclinical anti-NB activity compared to other tested CAR constructs. This enhanced activity was associated with an enrichment of CD8+ effector T cells in the tumor-microenvironment and upregulation of several effector molecules such as GNLY, GZMB, ZNF683, and HMGN2. Finally, we also showed that the CT3.28H.BBζ CAR was more potent than a recently clinically tested GD2-targeted CAR to control NB in vivo. Conclusion: Given the robust preclinical activity of CT3.28H.BBζ, these promising results warrant further clinical testing in children with NB.

2023-01-18 | GSE212658 | GEO

Inactivation of interferon signaling promotes the establishment of an immunosuppressive microenvironment in colorectal cancers

Project description:Tumors arise and grow despite anti-cancer immune responses. These responses can be stimulated by immunotherapies such as immune checkpoint inhibitors (e.g. anti-PD1 antibodies) and chimeric antigen receptors (CAR). Efficacy of these agents in solid tumors including colorectal cancers (CRC) is limited by immunosuppressive tumor microenvironment (TME) that prevents killing of malignant cells by cytotoxic T lymphocytes (CTL). Understanding the nature of TME-generated immunosuppression is of paramount importance. Here we report that TME elicited immunosuppression via eliminating activated CTL; this elimination required TME stress-induced downregulation of the IFNAR1 chain of type I interferon (IFN) receptor and attenuation of its signaling. Downregulation of IFNAR1 was observed in human colorectal cancers (CRC) and in mouse CRC models where it was required for efficient tumor development and progression. Stabilization of IFNAR1 on CTL improved their survival and increased anti- tumor activities of CAR T cells and PD1 inhibitors thereby providing a rationale for targeting IFNAR1 degradation for immunotherapies optimization. Two genotypes of mice were examined either 9 or 21 days post injection of MC38 colon cancer cells or MC38mRFP cells, respectively. 2-3 replicate mice were analyzed on separate arrays for each condition. 6 conditions in total were analyzed.

2016-01-15 | E-GEOD-76889 | biostudies-arrayexpress

The immune suppressive tumor microenvironment affects efficacy of radio-immunotherapy in breast-to-brain metastasis

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2021-02-12 | GSE164049 | GEO

Nasopharyngeal carcinoma patient samples: radio-sensitive samples vs. radio-resistant samples

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2013-09-21 | E-GEOD-32389 | biostudies-arrayexpress

Regulatory T cells underlies resistance to radio-immunotherapy, prevent the formation of tertiary lymphoid structures and impair CD8 T cell activation in glioblastoma

Project description:Glioblastomas (GBM) are aggressive primary brain tumors with an inherent resistance to T cell-centric immunotherapy imparted to their low mutational burden and immunosuppressive tumor microenvironment (TME). Examination of the GBM TME dynamics following fractionated RT revealed a 10-fold increase in T cell content, an enrichment also observed by spatial imaging mass cytometry in matched primary and recurrent human GBM. Implementation of a-PD-1 treatment at the peak of T cell infiltration results in a modest, albeit distinct survival benefit compared to concurrent a-PD-1 administration in GBM-bearing mice. CD103+ Tregs presenting increased cholesterol pathway activity are recruited to the GBM TME in response to a-PD-1 therapy, suggestive of their ability to restrain the response to immune checkpoint blockade. Targeting of Tregs elicits the formation of tertiary lymphoid structures, enhanced CD8 T cell content and activation and enables the therapeutic efficacy of radio-immunotherapy. These results support the rational design of therapeutic regimens limiting the induction of immunosuppressive feedback pathways in order to unleash the efficacy of T-cell centric immunotherapy in glioblastoma.

2022-12-31 | GSE203260 | GEO

Targeting secreted MDK-mediated tryptophan/kynurenine metabolism enhances DLL3 CAR T therapy for SCLC

Project description:<p>Small cell lung cancer (SCLC) exhibits profound immunometabolic suppression that impairs antigen presentation and constrains immunotherapy efficacy. Through integrated multi-omics analyses of primary human SCLC tumors, we identified midkine (MDK) as a dominant tumor-secreted driver of immune evasion. Mechanistically, MDK activates STAT3 to induce indoleamine 2,3-dioxygenase 1 (IDO1), driving tryptophan-kynurenine metabolic reprogramming. This axis suppresses myeloid antigen presentation, reduces HLA class I expression, and impairs CD8+ T cell function, establishing a immunosuppressive tumor microenvironment (TME). We engineered DLL3-targeted CAR T cells secreting anti-MDK scFv. These dual-functional CAR T cells neutralize MDK within the TME, restore antigen presentation, alleviate metabolic suppression, and reinvigorate CD8+ T cell responses. In SCLC models, they exhibited markedly enhanced antitumor activity, improved metabolic fitness, and durable immune activation without systemic toxicity. Collectively, our findings identify MDK as a key immunometabolic regulator and support sMDK-DLL3 CAR T cells as a targeted immunotherapy for SCLC.</p>

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Nasopharyngeal carcinoma patient samples: radio-sensitive samples vs. radio-resistant samples

Project description:Expression profiling of nasopharyngeal carcinoma patients comparing radio-sensitive samples with radio-resistant samples.

2013-09-21 | GSE32389 | GEO

Reprogramming the neuroblastoma tumor immune microenvironment to enhance GPC2 CAR T cells

Project description:Poor tumor trafficking and the immunosuppressive tumor microenvironment (TME) limit chimeric antigen receptor (CAR) T cell efficacy in solid tumors, such as neuroblastoma. We previously optimized GPC2 CARs in human neuroblastoma xenografts leading to clinical translation, however, there have not been preclinical studies using immunocompetent models. Thus, here we generated murine GPC2 CAR T cells using the D3-GPC2-targeting single-chain variable fragment being utilized clinically (NCT05650749) and tested them in neuroblastoma syngeneic allografts. Immune profiling of GPC2 CAR T cell-treated tumors revealed significant reprogramming of the TME, most notably poor intra-tumor CAR T cell persistence being associated with increased recruitment of myeloid-derived suppressor cells (MDSCs), along with MDSC-recruiting CXCL1/2 chemokines. These tumor-infiltrating MDSCs directly inhibited GPC2 CAR T cell activation and proliferation ex vivo. To both capitalize on this chemokine gradient and mitigate MDSC-tumor trafficking, we engineered GPC2 CAR T cells to express the CXCL1/2 receptor, CXCR2. CXCR2-armored GPC2 CAR T cells migrated towards CXCL1/2 gradients, enhanced anti-neuroblastoma efficacy, and reduced the level of MDSCs in the TME. Together, these findings suggest CAR T cell studies in immunocompetent models are imperative to define mechanisms of solid tumor immune escape and rationally design armoring strategies that will lead to durable clinical efficacy.

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