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The target antigen determines the mechanism of acquired resistance to T cell based therapies

ABSTRACT: The target antigen determines the mechanism of acquired resistance to T cell based therapies

PROVIDER: PRJNA866375 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR20853700_1.fastq.gz	Fastqsanger.gz
	SRR20853700_2.fastq.gz	Fastqsanger.gz
	SRR20853701_1.fastq.gz	Fastqsanger.gz
	SRR20853701_2.fastq.gz	Fastqsanger.gz
	SRR20853702_1.fastq.gz	Fastqsanger.gz

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The target antigen determines the mechanism of acquired resistance to T cell based therapies

Project description:Immunotherapy is a revolution in cancer treatment. Despite its success, cancer patients eventually progress due to the emergence of resistance. In this scenario, the selection of the tumor antigen is important and can be decisive in the success of the clinical response, particularly when resistance emerge. T cell bispecific antibodies (TCBs) are engineered molecules that include, within a single entity, binding sites to the T cell receptor and to a tumor-specific or a tumor-associated antigen. It is assumed that, as all TCBs have the same mechanism of action, mechanisms of resistance are independent of the tumor antigen. Using gastric CEA+/HER2+ MKN45 cells as a model and TCBs directed against CEA or HER2, here we show that the mechanism of resistance to a T cell-based therapy is dependent on the tumor antigen. Acquired resistant models to a high-affinity CEA-targeted TCB exhibit a reduction of CEA antigen levels due to transcriptional silencing, which is reversible upon 5-AZA treatment in vitro and in vivo. In contrast, a HER2-TCB resistant model maintains HER2 levels as HER2 downregulation led to an impairment of proliferation. Furthermore, using this latter model, we identify the disruption of the interferon-gamma signaling as the cause of resistance to killing by active T lymphocytes. Our results unveil different mechanisms of acquired resistance to TCBs depending on the selected antigen, which will help in the design of combinatorial strategies to increase the efficacy of cancer immunotherapies and to anticipate and overcome resistances.

2022-12-23 | GSE210592 | GEO

Acquired HER2 mutations in ER+ metastatic breast cancer confer resistance to ER-directed therapies

Project description:Estrogen receptor positive (ER+) breast cancers that develop resistance to therapies that target the ER are the most common cause of breast cancer death. Beyond mutations in ER, which occur in 25-30% of patients treated with aromatase inhibitors (AIs), our understanding of clinical mechanisms of resistance to ER-directed therapies remains incomplete. We identified activating HER2 mutations in metastatic biopsies from eight patients with ER+ metastatic breast cancer who had developed resistance to ER-directed agents, including AIs, tamoxifen, and fulvestrant. Examination of treatment-naïve primary tumors in five patients revealed no evidence of pre-existing mutations in four of five patients, suggesting that these mutations were acquired under the selective pressure of ER-directed therapy. These mutations were mutually exclusive with ER mutations, suggesting a distinct mechanism of acquired resistance to ER-directed therapies. In vitro analysis confirmed that these mutations conferred estrogen independence. In addition, and in contrast to ER mutations, these mutations resulted in resistance to tamoxifen, fulvestrant, and the CDK4/6 inhibitor palbociclib. Resistance was overcome by combining ER-directed therapy with the irreversible HER2 kinase inhibitor neratinib, highlighting an effective treatment strategy in these patients.

2018-10-19 | GSE121411 | GEO

Acquired HER2 mutations in ER+ metastatic breast cancer confer resistance to ER-directed therapies

Project description:Acquired HER2 mutations in ER+ metastatic breast cancer confer resistance to ER-directed therapies

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Transgenerational inheritance of acquired memory and epigenetic imprints through maternal gametes

Project description:Transgenerational inheritance of acquired traits/characteristics from ancestors is believed to play important roles in evolution, as well as health problems/symptoms not due to “classical genetic inheritance”. However, the central enigma, such as how the acquired transgenerational characteristics are developed, and how the acquired traits are transmitted from generations to generations of offspring, largely remained veiled. In this study, we used C elegans as a model system and provide evidence that the dynamic of H3K27me3 as a hallmark and regulator for the gut-mediated transgenerational inheritance of acquired traits. Further, we demonstrate that yolk proteins guide the establishment of the acquired epigenetic imprints in soma, as well as determines the transgenerational inheritance of epigenetic imprints and subsequent acquired behavior in offspring by maternal provision. Taken together, our findings support that yolk proteins both function as a systemic “non-nuclear factor” for establishing the somatic epigenetic imprints and as a “cargo” to transmit acquired epigenetic information to the subsequent generations through oocytes.

2022-09-10 | GSE138059 | GEO

FcγR engagement reprograms neutrophils into antigen cross-presenting cells that elicit acquired anti-tumor immunity

Project description:FcγR engagement reprograms neutrophils into antigen cross-presenting cells that elicit acquired anti-tumor immunity

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IKAROS facilitates antigen escape in the face of CD19- and CD22-targeted therapies for B-cell malignancies

Project description:IKAROS facilitates antigen escape in the face of CD19- and CD22-targeted therapies for B-cell malignancies

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Biomimetic Cell Stimulation with Graphene Oxide Antigen Presenting Platform (GO-APP) for Developing T Cell-Based Therapies

Project description:Biomimetic Cell Stimulation with Graphene Oxide Antigen Presenting Platform (GO-APP) for Developing T Cell-Based Therapies

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Impaired HLA Class 1 Antigen Processing and Presentation as a Mechanism of Acquired Resistance to Immune Checkpoint Inhibitors in Lung Cancer

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Impaired HLA Class 1 Antigen Processing and Presentation as a Mechanism of Acquired Resistance to Immune Checkpoint Inhibitors in Lung Cancer

Project description:Impaired HLA Class 1 Antigen Processing and Presentation as a Mechanism of Acquired Resistance to Immune Checkpoint Inhibitors in Lung Cancer

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Anti-tumor activity and acquired resistance mechanism of Dovitinib (TKI258) in RET rearranged lung adenocarcinoma

Project description:RET rearrangement is a newly identified oncogenic mutation in lung adenocarcinoma (LADC). Activity of dovitinib (TKI258), a potent inhibitor of FGFR, VEGFR, and PDGFR, in RET-rearranged LADC has not been reported. The aims of the study are to explore anti-tumor effects and mechanisms of acquired resistance of dovitinib in RET-rearranged LADC. Using structural modeling and in vitro analysis, we demonstrated that dovitinib induced cell cycle arrest at G0/G1 phase and apoptosis by selective inhibition of RET kinase activity and ERK1/2 signaling in RET-rearranged LC-2/ad cells. Strong anti-tumor effect of dovitinib was observed in LC-2/ad tumor xenograft model. To identify the acquired resistance mechanisms to dovitinib, LC-2/ad cells were exposed to increasing concentrations of dovitinib to generate LC-2/ad DR cells. Gene set enrichment analysis of gene expression and receptor tyrosine kinase assay revealed that Src, a central gene in focal adhesion , was activated in LC-2/ad DR cells. Saracatinib, a src kinase inhibitor, suppressed ERK1/2 phosphorylation and growth of LC-2/ad DR cells. Taken together, these findings suggest that dovitinib can be a potential therapeutic option for RET-rearranged LADC, in which acquired resistance to dovitinib can be overcome by targeting Src. To identify potential mechanisms of acquired resistance to dovitinib, we established LC-2/ad DR cells with acquired resistance to dovitinib by exposing LC-2/ad cells to increasing doses of dovitinib. LC-2/ad DR cells showed strong resistance to dovitinib (IC50> 3 μmol/L). Next, LC-2/ad and LC-2/ad DR cells were subjected to genome-wide gene expression profiling using cDNA microarray.

2015-09-01 | E-GEOD-69226 | biostudies-arrayexpress

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