Dataset Information

Single-Cell Sequencing Reveals Trajectory of Tumor-Infiltrating Lymphocyte States in Pancreatic Cancer.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) has few effective treatments. Immunotherapy, an attractive alternative strategy, remains challenging with the lack of knowledge on the tumor-infiltrating lymphocyte (TIL) landscape in PDAC. To generate a reference of T-cell subpopulations, we profiled 80,000 T cells from 57 PDAC samples, 22 uninvolved/normal samples, and cultured TIL using single-cell transcriptomic and T-cell receptor analysis. These data revealed 20 cell states and heterogeneous distributions of TIL populations. The CD8+ TIL contained a putative transitional GZMK+ population based on T-cell receptor clonotype sharing, and cell-state trajectory analysis showed similarity to a GZMB+PRF1+ cytotoxic and a CXCL13+ dysfunctional population. Statistical analysis suggested that certain TIL states, such as dysfunctional and inhibitory populations, often occurred together. Finally, analysis of cultured TIL revealed that high-frequency clones from effector populations were preferentially expanded. These data provide a framework for understanding the PDAC TIL landscape for future TIL use in immunotherapy for PDAC.

Significance

To improve the efficacy of immunotherapy in PDAC, there is a great need to understand the PDAC TIL landscape. This study represents a reference of PDAC TIL subpopulations and their relationships and provides a foundation upon which to base future immunotherapeutic efforts. This article is highlighted in the In This Issue feature, p. 2221.

SUBMITTER: Schalck A

PROVIDER: S-EPMC9547957 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Single-Cell Sequencing Reveals Trajectory of Tumor-Infiltrating Lymphocyte States in Pancreatic Cancer.

Schalck Aislyn A Sakellariou-Thompson Donastas D Forget Marie-Andrée MA Sei Emi E Hughes Tara G TG Reuben Alexandre A Bai Shanshan S Hu Min M Kumar Tapsi T Hurd Mark W MW Katz Matthew H G MHG Tzeng Ching-Wei D CD Pant Shubham S Javle Milind M Fogelman David R DR Maitra Anirban A Haymaker Cara L CL Kim Michael P MP Navin Nicholas E NE Bernatchez Chantale C

Cancer discovery 20221001 10

Pancreatic ductal adenocarcinoma (PDAC) has few effective treatments. Immunotherapy, an attractive alternative strategy, remains challenging with the lack of knowledge on the tumor-infiltrating lymphocyte (TIL) landscape in PDAC. To generate a reference of T-cell subpopulations, we profiled 80,000 T cells from 57 PDAC samples, 22 uninvolved/normal samples, and cultured TIL using single-cell transcriptomic and T-cell receptor analysis. These data revealed 20 cell states and heterogeneous distribu ...[more]

PMID: 35849783

Similar Datasets

Project description:BACKGROUND:Human pancreatic ductal adenocarcinoma (PDAC) responds poorly to immune checkpoint inhibitor (ICPi). While the mechanism is not completely clear, it has been recognized that tumor microenvironment (TME) plays key roles. We investigated if targeting CD47 with a monoclonal antibody could enhance the response of PDAC to ICPi by altering the TME. METHODS:Using immunohistochemistry, we examined tumor-infiltrating CD68+ pan-macrophages (CD68+ M) and CD163+ M2 macrophages (CD163+ M2) and tumor expression of CD47 and PD-L1 proteins in 106 cases of PDAC. The efficacy of CD47 blockade was examined in xenograft models. CD45+ immune cells from syngeneic tumor models were subjected to single-cell RNA-sequencing (scRNA-seq) by using the 10x Genomics pipeline. RESULTS:We found that CD47 expression correlated with the level of CD68+ M but not CD163+ M2. High levels of tumor-infiltrating CD68+ M, CD163+ M2, and CD47 expression were significantly associated with worse survival. CD47high/CD68+ Mhigh and CD47high/CD163+ M2high correlated significantly with shorter survival, whereas CD47low/CD68+ Mlow and CD47low/CD163+ M2low correlated with longer survival. Intriguingly, CD47 blockade decreased the tumor burden in the Panc02 but not in the MPC-83 syngeneic mouse model. Using scRNA-seq, we showed that anti-CD47 treatment significantly remodeled the intratumoral lymphocyte and macrophage compartments in Panc02 tumor-bearing mice by increasing the pro-inflammatory macrophages that exhibit anti-tumor function, while reducing the anti-inflammatory macrophages. Moreover, CD47 blockade not only increased the number of intratumoral CD8+ T cells, but also remodeled the T cell cluster toward a more activated one. Further, combination therapy targeting both CD47 and PD-L1 resulted in synergistic inhibition of PDAC growth in the MPC-83 but not in Panc02 model. MPC-83 but not Panc02 mice treated with both anti-CD47 and anti-PD-L1 showed increased number of PD-1+CD8+ T cells and enhanced expression of key immune activating genes. CONCLUSION:Our data indicate that CD47 targeting induces compartmental remodeling of tumor-infiltrating immune cells of the TME in PDAC. Different PDAC mouse models exhibited differential response to the anti-CD47 and anti-PD-L1 blockade due to the differential effect of this combination treatment on the infiltrating immune cells and key immune activating genes in the TME established by the different PDAC cell lines.

Project description:BackgroundThe tumor immune microenvironment (TIME) plays a pivotal role in determining ovarian cancer (OC) prognosis. Long non-coding RNAs (lncRNAs) are key regulators of immune response and tumor progression in OC. Among these, tumor-infiltrating B cells represent an emerging target in immune response pathways. However, the specific involvement of B cell-related lncRNAs (BCRLs) in OC remains unclarified.MethodsLeveraging single-cell and bulk RNA-sequencing data, correlation analysis identified BCRLs in ovarian serous cystadenocarcinoma (OV) from the TCGA database. Subsequently, BCRLIs were filtered through COX survival analysis and the LASSO algorithm, leading to the development of a B cell-related lncRNA scoring system (BCRLss). The predictive accuracy of BCRLss for prognosis in TCGA-OV was assessed and externally validated in an independent cohort. Functional enrichment analyses were conducted to elucidate biological pathways associated with risk subgroups. Additionally, the relationship between BCRLss and TIME was investigated through multiple algorithms and consensus clustering, uncovering potential immune response targets. Drug sensitivity analyses further identified potential therapeutic options tailored to risk subgroups. The highest risk score lncRNA was selected for in vitro validation.ResultsThe BCRLss was constructed using six BCRLIs. Survival analysis revealed an improved prognosis in the low-risk group, with results corroborated by external validation in the ICGC-OV cohort. ROC analysis and nomogram construction confirmed the strong prognostic accuracy of BCRLss. Enrichment analysis highlighted associations between risk subgroups and tumor immune pathways, with the low-risk group demonstrating a more robust immune response and elevated expression of immune checkpoint-related genes. Drug sensitivity tests revealed notable differences across risk subgroups. In vitro experiments confirmed elevated LINC01150 expression in OC cells, and LINC01150 knockdown significantly inhibited the proliferation, invasion, and migration of SKOV3 cells.ConclusionsIn conclusion, BCRLss provides a reliable prognostic tool for predicting clinical outcomes and the immune landscape of patients with OC, offering valuable guidance for immunotherapy target selection and personalized treatment strategies.

Dataset Information

Single-Cell Sequencing Reveals Trajectory of Tumor-Infiltrating Lymphocyte States in Pancreatic Cancer.

Significance

Publications

Single-Cell Sequencing Reveals Trajectory of Tumor-Infiltrating Lymphocyte States in Pancreatic Cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets