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The T cell receptor repertoire of tumor infiltrating T cells is predictive and prognostic for cancer survival.

ABSTRACT: Tumor infiltration by T cells is paramount for effective anti-cancer immune responses. We hypothesized that the T cell receptor (TCR) repertoire of tumor infiltrating T lymphocytes could therefore be indicative of the functional state of these cells and determine disease course at different stages in cancer progression. Here we show that the diversity of the TCR of tumor infiltrating T cell at baseline is prognostic in various cancers, whereas the TCR clonality of T cell infiltrating metastatic melanoma pre-treatment is predictive for activity and efficacy of PD1 blockade immunotherapy.

SUBMITTER: Valpione S

PROVIDER: S-EPMC8253860 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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The T cell receptor repertoire of tumor infiltrating T cells is predictive and prognostic for cancer survival.

Valpione Sara S Mundra Piyushkumar A PA Galvani Elena E Campana Luca G LG Lorigan Paul P De Rosa Francesco F Gupta Avinash A Weightman John J Mills Sarah S Dhomen Nathalie N Marais Richard R

Nature communications 20210702 1

Tumor infiltration by T cells is paramount for effective anti-cancer immune responses. We hypothesized that the T cell receptor (TCR) repertoire of tumor infiltrating T lymphocytes could therefore be indicative of the functional state of these cells and determine disease course at different stages in cancer progression. Here we show that the diversity of the TCR of tumor infiltrating T cell at baseline is prognostic in various cancers, whereas the TCR clonality of T cell infiltrating metastatic ...[more]

PMID: 34215730

Similar Datasets

The T cell receptor repertoire of tumor infiltrating T cells is predictive and prognostic for cancer survival

Project description:Tumor infiltration by T cells is paramount for effective anti-cancer immune responses. We hypothesized that the T cell receptor (TCR) repertoire of tumor infiltrating T lymphocytes (TIL/Tc) could determine disease course at different stages in cancer progression. We show that the diversity of the TIL/Tc TCR at baseline is prognostic in various cancers, whereas in metastatic melanoma TIL/Tc TCR clonality at baseline is predictive for activity and efficacy of PD1 blockade immunotherapy.

| EGAS00001005201 | EGA

T cell receptor β-chain repertoire analysis of tumor-infiltrating lymphocytes in pancreatic cancer.

Project description:Pancreatic cancer is lethal due to lack of perceptible symptoms and effective treatment methods. Immunotherapy may provide promising therapeutic choices for malignant tumors like pancreatic cancer. Tumor-infiltrating lymphocytes (TIL) in tumor mesenchyme could recognize peptide antigens presented on the surface of tumor cells. The present study aimed to test the relationship between the T cell receptor (TCR) β repertoire of the tumor and peripheral blood, and also to investigate the intra-tumor spatial heterogeneity of the TCR β repertoire in pancreatic cancer. To the best of our knowledge, this is the first study to evaluate the clonal composition of TCR β repertoire in TIL across the spatial extent of pancreatic cancer. In this study, we studied 5 patients who were diagnosed with primary pancreatic cancer. Ultra-deep sequencing was used to assess the rearrangement of the TCR β-chain (TCR β) gene. HE staining and immunohistochemistry of CD3, CD4, CD8 and HLA class I were used to show histopathology and immune conditions macroscopically. TIL repertoire showed that different regions of the same tumor showed a greater number of repertoire overlaps between each other than between peripheral blood, which suggested that T cell clones in pancreatic cancer might be quite different from those in peripheral blood. In contrast, intra-tumoral TCR β repertoires were spatially homogeneous between different regions of a single tumor tissue. Based on these results, we speculated that the cellular adaptive immune response in pancreatic cancer was spatially homogeneous; this may pave the way for immunotherapy for the treatment of pancreatic cancer patients.

| S-EPMC6317932 | biostudies-literature

Characterization of the T-cell receptor beta chain repertoire in tumor-infiltrating lymphocytes.

Project description:Tumor-infiltrating lymphocytes (TILs) are direct effectors of tumor immunity, and their characterization is important for further development of immunotherapy. Recent advances in high-throughput sequencing technologies have enabled a comprehensive analysis of T-cell receptor (TCR) complementarity-determining region 3 (CDR3) sequences, which may provide information of therapeutic importance. We developed a high-fidelity target sequencing method with the ability for absolute quantitation, and performed large-scale sequencing of TCR beta chain (TCRB) CDR3 regions in TILs and peripheral blood lymphocytes (PBLs). The estimated TCRB repertoire sizes of PBLs from four healthy individuals and TILs from four colorectal cancer tissue samples were 608,664-1,003,098 and 90,228-223,757, respectively. The usage of J- and V-regions was similar in PBLs and TILs. Proportions of CDR3 amino acid (aa) sequences occupying more than 0.01% of the total molecular population were 0.33-0.43% in PBLs and 1.3-3.6% in TILs. Additional low coverage sequencing of 15 samples identified five CDR3 aa sequences that were shared by nine patients, one sequence shared by 10 patients, and one sequence shared by 12 patients. The estimated size of the TCRB repertoire in TILs was significantly smaller than that in PBLs. The proportion of abundant species (>0.01%) in TILs was larger than that in PBLs. Shared CDR3 aa sequences represent a response to common antigens, and the identification of such CDR3 sequences may be beneficial in developing clinical biomarkers.

| S-EPMC5055180 | biostudies-literature

T cell receptor repertoire analysis of tumor-infiltrating T cells in non-small cell lung cancer

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-03-11 | GSE151538 | GEO

Tumor-Infiltrating B- and T-Cell Repertoire in Pancreatic Cancer Associated With Host and Tumor Features.

Project description:BackgroundInfiltrating B and T cells have been observed in several tumor tissues, including pancreatic ductal adenocarcinoma (PDAC). The majority known PDAC risk factors point to a chronic inflammatory process leading to different forms of immunological infiltration. Understanding pancreatic tumor infiltration may lead to improved knowledge of this devastating disease.MethodsWe extracted the immunoglobulins (IGs) and T cell receptors (TCRs) from RNA-sequencing of 144 PDAC from TCGA and 180 pancreatic normal tissue from GTEx. We used Shannon entropy to find differences in IG/TCR diversity. We performed a clonotype analysis considering the IG clone definition (same V and J segments, same CDR3 length, and 90% nucleotide identity between CDR3s) to study differences among the tumor samples. Finally, we performed an association analysis to find host and tumor factors associated with the IG/TCR.ResultsPDAC presented a richer and more diverse IG and TCR infiltration than normal pancreatic tissue. A higher IG infiltration was present in heavy smokers and females and it was associated with better overall survival. In addition, specific IG clonotypes classified samples with better prognosis explaining 24% of the prognosis phenotypic variance. On the other hand, a larger TCR infiltration was present in patients with previous history of diabetes and was associated with lower nonantigen load.ConclusionsOur findings support PDAC subtyping according to its immune repertoire landscape with a potential impact on the understanding of the inflammatory basis of PDAC risk factors as well as the design of treatment options and prognosis monitoring.

| S-EPMC8495220 | biostudies-literature

Tumor-infiltrating exhausted CD8+ T cells dictate reduced survival in premenopausal estrogen receptor-positive breast cancer.

Project description:CD8+ tumor-infiltrating lymphocytes (TILs) are associated with improved survival in triple-negative breast cancer (TNBC) yet have no association with survival in estrogen receptor-positive (ER+) BC. The basis for these contrasting findings remains elusive. We identified subsets of BC tumors infiltrated by CD8+ T cells with characteristic features of exhausted T cells (TEX). Tumors with abundant CD8+ TEX exhibited a distinct tumor microenvironment marked by amplified interferon-γ signaling-related pathways and higher programmed death ligand 1 expression. Paradoxically, higher levels of tumor-infiltrating CD8+ TEX associated with decreased overall survival of patients with ER+ BC but not patients with TNBC. Moreover, high tumor expression of a CD8+ TEX signature identified dramatically reduced survival in premenopausal, but not postmenopausal, patients with ER+ BC. Finally, we demonstrated the value of a tumor TEX signature score in identifying high-risk premenopausal ER+ BC patients among those with intermediate Oncotype DX Breast Recurrence Scores. Our data highlight the complex relationship between CD8+ TILs, interferon-γ signaling, and ER status in BC patient survival. This work identifies tumor-infiltrating CD8+ TEX as a key feature of reduced survival outcomes in premenopausal patients with early-stage ER+ BC.

| S-EPMC8855819 | biostudies-literature

The Glioma-Infiltrating T Cell Receptor Repertoire

Project description:While immune signaling has emerged as a defining feature of the glioma microenvironment, local selection of responding T cells and their anti-tumor potential as a population are difficult to measure directly in patients. High-throughput sequencing of T cell receptor repertoires (TCRseq) provides a population-wide statistical description of how T cells respond to disease. Here, we define new immunophenotypes in glioma based on TCRseq and RNA-Seq of tumor tissue, non-neoplastic brain tissue, and peripheral blood from patients. Using information theory, we characterize antigen-driven selection in glioma and its relationship with the expression of distinct immune-functional pathways in the tumor microenvironment. Finally, we identify a strong relationship between usage of certain TCR in peripheral blood and the divergence of the infiltrating T cell population from the peripheral repertoire. We anticipate that these immunophenotypes will be foundational to monitoring and predicting response to anti-glioma vaccines and immunotherapy. We characterized the T cell receptor (TCR) repertoires of 11 high-grade glioma patients, three low-grade glioma patients, and thee non-glioma patients by TCRseq of brain-infiltrating T cells and matching peripheral blood. In addition, we obtained gene expression profiles from brain tissue of each patient by RNA-Seq. We additionally measured the TCR repertoires exclusively from peripheral blood of one additional non-glioma patient.

2016-05-18 | E-GEOD-79338 | biostudies-arrayexpress

Landscape of tumor-infiltrating T cell repertoire of human cancers.

Project description:We developed a computational method to infer the complementarity-determining region 3 (CDR3) sequences of tumor-infiltrating T cells in 9,142 RNA-seq samples across 29 cancer types. We identified over 600,000 CDR3 sequences, including 15% that were full length. CDR3 sequence length distribution and amino acid conservation, as well as variable gene usage, for infiltrating T cells in many tumors, except in brain and kidney cancers, resembled those for peripheral blood cells from healthy donors. We observed a strong association between T cell diversity and tumor mutation load, and we predicted SPAG5 and TSSK6 as putative immunogenic cancer/testis antigens in multiple cancers. Finally, we identified three potential immunogenic somatic mutations on the basis of their co-occurrence with CDR3 sequences. One of them, a PRAMEF4 mutation encoding p.Phe300Val, was predicted to result in peptide binding strongly to both MHC class I and class II molecules, with matched HLA types in its carriers. Our analyses have the potential to simultaneously identify immunogenic neoantigens and tumor-reactive T cell clonotypes.

| S-EPMC5298896 | biostudies-literature

ITGAE Defines CD8+ Tumor-Infiltrating Lymphocytes Predicting a better Prognostic Survival in Colorectal Cancer.

Project description:BackgroundTumor-infiltrating lymphocytes (TIL) in colorectal tumor tissue are significantly correlated with a favorable prognosis, such as CD8+ lymphocytes, which are also called tumor-reactive lymphocytes. However, not all tumor-infiltrating T cells confer benefit to patients. Therefore, it is of substantial benefit to identify a biomarker to demarcate these tumor-reactive lymphocytes.MethodsWe investigated whether ITGAE could be used to discriminate reactive CD8+ lymphocytes in colorectal cancer (CRC). TCGA colorectal cancer data sets (n1 = 492, n2 = 386) and FUSCC set (n3 = 276) were used in this study. Further phenotyping of ITGAE+ cells and the mechanistic basis were investigated.FindingsIn the training and testing sets from TCGA, ITGAE expression, which is strongly correlated with cytotoxic T cell markers (CD8/CD3/PD1), independently predicted longer disease-free survival (DFS) and overall survival (OS). In line with this, the association between ITGAE+ lymphocytes and survival has been confirmed in the FUSCC cohort for validation (P = .026). ITGAE + cells in the series always co-stained with CD8 were preferentially located in the tumor. Interestingly, ITGAE+ lymphocytes tended to associate with the epithelial-mesenchymal transition (EMT) with decreased Snail and increased E-cadherin expression accompanied. Finally, gene set enrichment analysis showed that immune activation was significantly enriched in the high ITGAE+ TIL group, accompanied by enriched EMT-related pathways.InterpretationBecause of the specified expression of tumor-reactive CD8+ T-cells, ITGAE may be a promising biomarker for the rapid identification of immune infiltration in CRC.

| S-EPMC6154785 | biostudies-literature

T cell receptor repertoire analysis of tumor-infiltrating T cells in non-small cell lung cancer [tet_sorted_PBLT_cells]

Project description:We analyzed 778,938 T cell receptor (TCR) CDR3b sequences from 178 non-small cell lung cancer (NSCLC) patients using GLIPH2 (Grouping of Lymphocyte Interactions with Paratope Hotspots 2). We identified over 66,000 TCR shared specificity groups, of which over 400 were enriched in tumor vs. adjacent lung. We focused on one tumor-enriched specificity group and used a yeast display library to identify the peptide epitopes. These include peptides from TMEM161A, which is an overexpressed antigen in NSCLC, and homologous peptides from Epstein-Barr virus (EBV) and E. coli, aligning with recent reports of virus-specific T cells in tumor infiltrates. Overall, we analyzed a very large dataset of TCR sequences from NSCLC patients and found thousands of specificities shared by three or more patients. This creates a database of TCR shared specificity groups in NSCLC, and also a template for mining and understanding the specificity of infiltrating T cells for any cancer.

2021-03-11 | GSE151531 | GEO

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