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Expansion of peripheral T cell clonotypes predict response in patients with small cell neuroendocrine bladder and prostate cancers treated with chemo-immunotherapy in a phase I clinical trial [bulkRNA-Seq]

ABSTRACT: To explore the impact of immunotherapy, we report a single institution, dual cohort phase Ib study (NCT 03582475) of platinum-based chemotherapy in combination with PD-1 antagonist pembrolizumab to evaluate safety and preliminary efficacy in patients with small cell bladder and small cell/neuroendocrine prostate cancers. To assess the immunologic basis for responses, single cell gene expression and T cell receptor (TCR) sequencing of serial peripheral blood samples revealed a diverse T cell repertoire with expansion of large clonotypes correlating with response.

ORGANISM(S): Homo sapiens

PROVIDER: GSE273798 | GEO | 2024/10/11

REPOSITORIES: GEO

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Expansion of peripheral T cell clonotypes predict response in patients with small cell neuroendocrine bladder and prostate cancers treated with chemo-immunotherapy in a phase I clinical trial

Project description:To explore the impact of immunotherapy, we report a single institution, dual cohort phase Ib study (NCT 03582475) of platinum-based chemotherapy in combination with PD-1 antagonist pembrolizumab to evaluate safety and preliminary efficacy in patients with small cell bladder and small cell/neuroendocrine prostate cancers. To assess the immunologic basis for responses, single cell gene expression and T cell receptor (TCR) sequencing of serial peripheral blood samples revealed a diverse T cell repertoire with expansion of large clonotypes correlating with response.

2024-10-10 | GSE266079 | GEO

MR1-restricted T cell clonotypes are associated with “resistance” to Mycobacterium tuberculosis infection

Project description:T cells are required for protective immunity against Mycobacterium tuberculosis. We recently described a cohort of Ugandan household contacts of tuberculosis cases who appear to “resist” M. tuberculosis infection (resisters; RSTRs) and showed that these individuals harbor IFN-γ–independent T cell responses to M. tuberculosis–specific peptide antigens. However, T cells also recognize nonprotein antigens via antigen-presenting systems that are independent of genetic background, known as donor-unrestricted T cells (DURTs). We used tetramer staining and flow cytometry to characterize the association between DURTs and “resistance” to M. tuberculosis infection. Peripheral frequencies of most DURT subsets were comparable between RSTRs and latently infected controls (LTBIs). However, we observed a 1.65-fold increase in frequency of MR1-restricted T (MR1T) cells among RSTRs in comparison with LTBIs. Single-cell RNA sequencing of 18,251 MR1T cells sorted from 8 donors revealed 5,150 clonotypes that expressed a common transcriptional program, the majority of which were private. Sequencing of the T cell receptor α/T cell receptor δ (TCRα/δ) repertoire revealed several DURT clonotypes were expanded among RSTRs, including 2 MR1T clonotypes that recognized mycobacteria-infected cells in a TCR-dependent manner. Overall, our data reveal unexpected donor-specific diversity in the TCR repertoire of human MR1T cells as well as associations between mycobacteria-reactive MR1T clonotypes and resistance to M. tuberculosis infection.

2024-05-08 | GSE264592 | GEO

A phase Ib trial evaluating the safety, efficacy, and immunologic effects of pembrolizumab plus paclitaxel or flat-dose capecitabine in 1st/2nd line metastatic triple-negative breast cancer

Project description:Chemoimmunotherapy with anti-programmed cell death 1/ligand 1 and cytotoxic chemotherapy is a promising therapeutic modality for women with triple-negative breast cancer, but questions remain regarding optimal chemotherapy backbone and biomarkers for patient selection. We report final outcomes from a phase Ib trial evaluating pembrolizumab (200mg IV every 3 weeks) with either weekly paclitaxel (80mg/m2 weekly) or flat-dose capecitabine (2000mg orally twice daily for 7 days of every 14-day cycle) in the 1st/2nd line setting. The primary endpoint is safety (receipt of 2 cycles without grade III/IV toxicities requiring discontinuation or ≥21-day delays). The secondary endpoint is efficacy (week 12 objective response). Exploratory aims are to characterize immunologic effects of treatment over time, and to evaluate novel biomarkers. The trial demonstrates that both regimens meet the pre-specified safety endpoint (paclitaxel: 87%; capecitabine: 100%). Objective response rate is 29% for pembrolizumab/paclitaxel (n=4/13, 95% CI: 10-61%) and 43% for pembrolizumab/capecitabine (n=6/14, 95% CI: 18-71%). Partial responses are observed in two subjects with chemo-refractory metaplastic carcinoma (both in capecitabine arm). Both regimens are associated with significant peripheral leukocyte contraction over time. Response is associated with clinical PD-L1 score, non-receipt of prior chemotherapy, and the H&E stromal tumor infiltrating lymphocyte score, but also by a novel 27 gene IO score and spatial biomarkers (lymphocyte spatial skewness). In conclusion, pembrolizumab with paclitaxel or capecitabine is safe and clinically active. Both regimens are lymphodepleting, highlighting the competing immunostimulatory versus lymphotoxic effects of cytotoxic chemotherapy. Further exploration of the IO score and spatial TIL biomarkers is warranted.

2023-02-17 | GSE225078 | GEO

Transcriptome-based identification of tumor-reactive and bystander CD8+ T cell receptor clonotypes in human pancreatic cancer

Project description:Pancreatic ductal adenocarcinoma (PDAC) is generally refractory to immune checkpoint blockade, although patients with genetically unstable tumors can show modest therapeutic benefit. We previously demonstrated the presence of tumor-reactive CD8+ T cells in PDAC samples. Here, we charted the tumor-infiltrating T cell repertoire in PDAC by combining single-cell transcriptomics with functional testing of T cell receptors (TCRs) for reactivity against autologous tumor cells. On the basis of a comprehensive dataset including 93 tumor-reactive and 65 bystander TCR clonotypes, we delineated a gene signature that effectively distinguishes between these T cell subsets in PDAC, as well as in other tumor indications. This revealed a high frequency of tumor-reactive TCR clonotypes in three genetically unstable samples. In contrast, the T cell repertoire in six genetically stable PDAC tumors was largely dominated by bystander T cells. Nevertheless, multiple tumor-reactive TCRs were successfully identified in each of these samples, thereby providing a perspective for personalized immunotherapy in this treatment-resistant indication.

2024-01-26 | GSE254250 | GEO

The self-reactive FVIII T cell repertoire in healthy individuals relies on a short set of epitopes and public clonotypes

Project description:Non-mutated FVIII-specific CD4 T cell epitopes have been recently found to contribute to the development of inhibitors in patients with hemophilia A (HA), while auto-reactive CD4 T cells specific to FVIII circulate in the blood of healthy individuals at a frequency close to the foreign protein Ovalbumin. Thus, although FVIII is a self-protein, the central tolerance raised against FVIII appears to be low. In this study, we conducted a comprehensive analysis of the FVIII CD4 T cell repertoire in twenty-nine healthy donors. Sequencing of the CDR3β TCR region from isolated FVIII-specific CD4 T cells revealed a limited usage and pairing of TRBV and TRBJ genes, as well as a mostly hydrophobic composition of the CDR3β region according to their auto-reactivity. FVIII repertoire is dominated by a few clonotypes, with only 13 clonotypes accounting for half of the FVIII response. Through a large-scale epitope mapping of the full-length FVIII sequence, we identified 18 immunodominant epitopes located in the A1, A3, C1, and C2 domains and covering half of the T-cell response. These epitopes exhibited a broad specificity for HLA-DR or DP molecules or both. T-cell priming with this reduced set of peptides revealed that highly expanded clonotypes specific to these epitopes were responsible individually for up to 32% of the total FVIII repertoire. These FVIII T cell epitopes and clonotypes were shared among HLA-unrelated donors tested and previously reported HA patients. Our study highlights the role of the auto-reactive T cell response against FVIII in HA and its similarity to the response observed in healthy individuals. Thus, it provides valuable insights for the development of new tolerance induction and deimmunization strategies

2024-01-22 | GSE253521 | GEO

Stereotypic persistent B cell receptor clonotypes in Alzheimer’s Disease

Project description:The growing evidence suggest that the effect of Alzheimer’s Disease (AD) is not solely restricted to the brain. Numerous groups investigated the relation between the central nervous system and peripheral system, whereupon the peripheral system is closely involved in accordance with the progression of disease and systemic immunity. In our previous report, we identified shared B cell receptor (BCR) sequences among 10 AD patients which showed similar class-switching orientation, identical isotypes and high somatic hypermutation rate. For further investigation, we recruited 44 patients with AD at baseline and 37 patients for second follow-up to identify the shared BCR sequences among patients and persistent BCR within an individual patient. We were able to annotate 3983 unique AD specific BCR clonotypes and one of the clonotype showed binding affinity against human Aβ42 peptide. Our finding can provide evidence of common BCRs in AD patients exposed to antigenic stimulus which are related to AD pathogenesis.

2023-09-13 | GSE242738 | GEO

Expansion of Tumor-Infiltrating CD8+ T Cell Clonotypes Occurs in the Spleen in Response to Immune Checkpoint Blockade

Project description:Immune checkpoint blockade (ICB) enhances tumor-reactive T cell responses against cancer, leading to long-term tumor control and survival in a fraction of patients. Given the increasingly recognized complexity of CD8+ T cell differentiation that occurs in response to chronic antigen stimulation, it remains unclear precisely which T cell differentiation states are critical for the response to ICB, as well as the anatomic sites at which ICB-mediated reinvigoration of these T cells occurs. We used paired single-cell RNA and T cell receptor (TCR) sequencing to profile endogenous, tumor-reactive CD8+ T cells isolated from tumors, tumor-draining lymph nodes, and spleens of mice treated with ICB. We identified an intermediate-exhausted population of T cells in the spleen which underwent the greatest expansion in response to ICB and gave rise to the majority of tumor-infiltrating clonotypes. Increasing concentrations of systemic antigen perturbed the differentiation of this phenotype towards an exhausted_KLR state, while a lack of cross-presentation of tumor-derived antigen blunted differentiation in the spleen. We identified an analogous population of exhausted_KLR CD8+ T cells in matched human tumor and blood samples that exhibited diminished tumor-trafficking ability. Collectively, our data demonstrate the critical role of antigen density within the spleen in coordinating the differentiation and expansion of tumor-infiltrating T cell clonotypes in response to ICB.

2024-07-19 | GSE270050 | GEO

Study of Pembrolizumab With Pemetrexed and Oxaliplatin in Chemo-Refractory Metastatic Colorectal Cancer Patients

Project description:This is a Phase Ib study to evaluate the safety and preliminary anti-tumor activity of pembrolizumab in combination with pemetrexed with or without oxaliplatin in patients with chemo-refractory microsatellite stable (MSS) metastatic colorectal cancer (mCRC) without any further standard treatment options.

| 2280743 | ecrin-mdr-crc

Identification of a novel Bromodomain / Casein Kinase II / TAF-containing complex as a regulator of mitotic condensin function

Project description:ABSTRACT: Condensin is a central regulator of mitotic genome structure, with mutants showing poorly condensed chromosomes and profound segregation defects. Here we identify the fission yeast NCT complex, comprising the Nrc1 BET-family tandem bromodomain protein (SPAC631.02), Casein Kinase II (CKII) and several TAFs, as a novel regulator of condensin function (where NCT mutants restore the formation of segregation-competent chromosomes in cells containing defective condensin). Synchronous ChIP-seq shows that NCT and condensin bind similar genomic regions, but only briefly co-localize during the periods of chromosome condensation and decondensation. These results are consistent with a model where NCT targets CKII to chromatin in a cell cycle-directed manner to modulate the activity of condensin during chromosome condensation and decondensation. DATA: Study includes ChIP-seq of fission yeast H3-K4Me3, H3-K36Me3, TBP, Taf7, Nrc1, Cka1 from aynchronous cells; Nrc1 and Cut3 (representing condensin) from four synchronized cell-cycle stages estimated as G2/M, Metaphase, Anaphase and G1/S.

2014-01-10 | E-GEOD-53955 | biostudies-arrayexpress

Expression data from syngeneic Hepa1-6 model in C57Bl/6J mice

Project description:Lenvatinib is an effective drug in advanced hepatocellular carcinoma (HCC). Its combination with the anti-PD1 immune checkpoint inhibitor pembrolizumab has achieved encouraging results in phase Ib and is currently being tested in phase III trials. Here, we aimed at exploring the molecular and immunomodulatory effects of lenvatinib alone or in combination with anti-PD1. We generated a syngeneic model of HCC in C57BL/6J mice and randomized the animals to receive placebo, lenvatinib, anti-PD1 or combination treatment. Transcriptomic analysis were performed to assess the expression profile of tumors from mice receiving each treatment strategy.

2023-04-07 | GSE153203 | GEO

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