ADAPTeR Study: scRNA and scTCR data from TILs from two ccRCC patients treated with anti-PD1
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PROVIDER: EGAS00001005640 | EGA |
REPOSITORIES: EGA
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Project description:Background: Cancer Immunotherapy with cytokines has demonstrated clinical efficacy but is frequently accompanied with severe adverse events caused by excessive and systemic immune activation. Here, we addressed these challenges by engineering a fusion protein of a single, potency-reduced, IL-15 mutein and an anti-PD1 antibody (αPD1-IL15m). This immunocytokine is designed to deliver PD1-mediated avidity-driven IL-2/15 receptor stimulation preferentially to PD1-positive tumor-infiltrating lymphocytes (TILs) while reducing the natural preference of IL-15 for circulating peripheral NK or T cell Methods: We isolated human lymphocytes from resected hepatocellular carcinoma tissue and cultured these tumor-infiltrating lymphocytes (TILs) in vitro in the presence or absence of an PD1-targeted IL15 mutein, anti-PD1 antibody or IL-15 agonist. After 9 days, CD4+ TILs and CD8+ TILs were sorted by FACS and RNA of 3,000 to 150,000 cells was isolated. Results: The PD1-IL15 fusion cytokine enhanced pro-survival, proliferation and activation pathways in tumor-infiltrating CD4+ and CD8+ cells compared to untreated controls as well as to the combined treatment of single agents (anti-PD1 antibody and IL-15 agonist)
2021-05-25 | GSE157893 | GEO
Project description:This study was a phase I/II trial initiated by the investigator to evaluate the safety and tolerability of anti-programmed cell death protein 1 (anti-PD1) antibody-activated autologous tumor-infiltrating lymphocytes (TILs) combined with adjuvant chemotherapy in participants with stage III colon cancer. Twenty participants were enrolled and anti-PD1 antibody-activated TILs was infused into participants after the final of adjuvant chemotherapy to assess the safety and 3-year disease-free survival.
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Project description:Gene expression profile at single cell level of human TILs treated with PD1-TIM3, PD1-LAG3, anti-PD1 or control isotype.
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Project description:CD8+ T cells isolated from HCC tissue were divided into three groups: PD1-TIM3- CD8+ TILs, exhibiting full effector function; PD1-intTIM3+ CD8+ TILs, exhibiting partial exhaustion; and PD1-hiTIM3+ CD8+ TILs, exhibiting severe exhaustion, as reflected by the differences in their ability to produce effector cytokines respectively. Transcriptome sequence analysis was performed to investigate the gene expression profile was performed.
2019-12-31 | E-MTAB-7278 | biostudies-arrayexpress
Project description:Background: Outcomes for locally advanced or recurrent/ metastatic head and neck squamous cell carcinomas (HNSCCs) remain unfavorable despite recent advances with immune checkpoint blockade (ICB). Preclinical studies using model antigens identified a critical role of CD8+TCF7+PD1+ T cells in anti-PD1 response. Studies on the heterogeneity and clonal dynamics of global tumor infiltrating T lymphocytes (TILs) in the HNSCC anti-PD1 and anti-CTLA4 response have not been explored. Results: In this study, we generated isogenic HNSCC anti-PD1 sensitive/resistant models that bore distinct cancer cell intrinsic transcriptomic programs. Tumor microenvironment characterization using mass cytometry and targeted depletion revealed the contribution of Tregs and M2-like macrophages in anti-PD1 resistance. Paired single-cell RNA and TCR sequencing on tumor infiltrating immune cells from ICB responsive and resistant HNSCC models identified a spectrum of CD8+ TIL subsets including TCF7+PD1- (naïve/memory-like), TCF7+PD1+ (progenitor exhausted), and TCF7-PD1+ (terminally exhausted). Mapping TCR shared fractions between these subsets identified that successful anti-PD1 or anti-CTLA4 therapy induced higher post-treatment T cell lineage transitions. A TIL differentiation gene signature was associated with better responses in multiple ICB clinical trials. Conclusions: Together, analyses integrating scRNAseq and TCRseq demonstrate distinct differentiation dynamics of CD8+ TILs in novel ICB responsive and resistant HNSCC models, highlighting critical aspects of CD8+ TIL differentiation in response to ICB.
2021-12-01 | GSE153383 | GEO
Project description:Combined nivolumab (anti-PD1) and relatlimab (anti-LAG3) have shown enhanced effectiveness in melanoma patients. However, how these two receptors work together to hinder anti-tumor immunity remains unclear. Our study demonstrates that PD1/LAG3-deficient CD8+ T cells with more effectively clearing tumors and survive longer in melanoma mouse models. These PD1/LAG3-deficient CD8+ T cells have unique transcriptional profiles, broad TCR clonality, and enriched effector-like and interferon-responsive genes, leading to increased IFN gamma release indicating functionality. PD1 and LAG3 together drive T cell exhaustion, with a significant impact on TOX modulation. Mechanistically, autocrine IFN gamma signaling is crucial for enhancing anti-tumor immunity in PD1/LAG3-deficient CD8+ T cells, providing insights into the enhanced efficacy of combined PD1 and LAG3 targeting.
2024-08-07 | GSE262740 | GEO
Project description:Functional impairment of the immune response to chronic viral infections and malignancies is characterised by exhausted T cells, which do not respond to antigen. The cell surface receptor PD1 has been implicated in the maintenance of T cell exhaustion and is an attractive target for immunomodulatory approaches to the treatment of such conditions. However, the mechanisms by which PD1 signalling causes exhaustion and the exact response of T cells to PD1 activation are not clear although it has been suggested that PD1 up regulates a number of anti-proliferative factors. Here we perform cytokine and transcriptional profiling of uninfected primary human T cells to characterise these events. We find that PD1 completely prevents cytokine and transcrip- tional changes induced by CD3/28 stimulation. We do not see any factors specifically induced by PD1, including BATF or IL10 which have previously been linked to PD1 activity. Together with the work of others this confirms that PD1 is the sole effector of T cell exhaustion and that infection is responsible for BATF and IL10 up regulation. As a consequence future therapeutic strategies will be confined to the inhibition of PD1 and not a downstream effector.
2012-04-01 | E-MEXP-3410 | biostudies-arrayexpress
Project description:Recent success in cancer immunotherapy has come from the blockade of inhibitory receptors on T cells, such as programmed cell death-1, which can induce a state of T cell exhaustion upon constant antigen stimulation. Understanding miRNA regulation of PD1 can be useful to discover miRNAs for use in therapy or as prognostic markers in various diseases including cancer, autoimmunity and transplantation. We used microarrays to discover global miRNA expression changes upon PD1 upregulation and identified miRNAs that are both up- and down-regulated. B16F10 cells were injected subcutaneously into C57BL/6 mice and 16 days later CD4+PD1+ and CD4+PD1- were sorted from the lymph nodes and spleen for RNA extraction and hybridization on Affymetrix miRNA array.
2015-08-01 | E-GEOD-65208 | biostudies-arrayexpress
Project description:Here we report a humanized clear cell renal cell carcinoma (ccRCC) orthotopic NSG-SGM3 mouse model (hccRCC-NSG-SGM3) with reconstituted human lymphocytes derived from fetal CD34+ hematopoietic stem cells (HSCs) bearing human ccRCC skrc-59 cells under the kidney capsule. Human leukocyte antigen (HLA) matched CD34+ HSCs were used for the humanization to reduce T cell alloreactivity against skrc-59 human ccRCC cells. Tumors were collected and sorted for CD45+ tumor infiltrated leukocytes (TILs) to profile the tumor microenvironment (TME) in hccRCC-NSG-SGM3. By comparing to patient data from prospective clinical trials of the anti-PD-1 monoclonal antibody (mAb) nivolumab in advanced ccRCC, the results demonstrated that the CD45+ TILs from hccRCC-NSG-SGM3 reconstitutes most CD45+ cell types, including NK cells, dendritic cells, exhausted CD8 T cells, regulatory T cells (Tregs), that are observed in advanced ccRCC patient TME. Furthermore, Anti-carbonic anhydrase IX (CAIX) G36 immune restoring (IR) chimeric antigen receptor (CAR) T cells secreting PD-L1 targeted immune checkpoint inhibitor (ICI) mAb (G36-PDL1) exhibited superior tumor control compared to G36 CAR-T cells with anti-SARS mAb (G36-SARS) and anti-BCMA A716 CAR-T cells with anti-PD-L1 mAb (A716-PDL1). In addition, G36-PDL1 CAR-T cells restored active anti-tumor immunity at tumor site uncovered by 10X genomics single cell RNA sequencing (scRNA-seq) and single cell T cell receptor sequencing (scTCR-seq).
2024-01-25 | GSE210664 | GEO
Project description:Mechanistic understanding of the immune checkpoint receptor PD1 is largely based on mouse models, but human and mouse PD1 orthologs exhibit only 59.6% identity in amino acid sequences, raising the question of potential cross-species functional differences. Based on our biochemical evidence that human PD1 is more inhibitory than mouse PD1, we addressed the functional consequence of PD1 humanization in a mouse melanoma model with adoptively transferred T cells. Using CITE-seq (cellular indexing of transcriptomes and epitopes by sequencing), we found that humanization of PD1 intracellular domain (ICD) in CD8 T cells decreases the numbers, effector functions, and differentiation of intratumoral T cells. Specifically, PD1 humanization reduced the number of effector-like exhausted T cell subset while increasing the precursor-exhausted T cell subset, the latter of which is known to respond to anti-PD(L)1 therapy.
2024-11-05 | GSE280853 | GEO