T Cells Expressing Receptor Recombination/Revision Machinery Are Detected in the Tumor Microenvironment and Expanded in Genomically Over-unstable Models

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RESEARCH PRODUCT

T Cells Expressing Receptor Recombination/Revision Machinery Are Detected in the Tumor Microenvironment and Expanded in Genomically Over-unstable Models

Alfonso Urso Daniele Greco Vito Amodio Claudia Chiodoni Daniele Lecis Laura La Paglia Mario P. Colombo Fabio Iannelli Francesco Ferrari Serenella M. Pupa Giancarlo Pruneri Federica Zanardi Antonino Fiannaca Giovanni Germano Sabina Sangaletti Claudio Tripodo Massimo La Rosa Valeria Cancila Alberto Bardelli Giulia Graziano Gaia Morello

subject

Cancer Research Datasets as Topic T-Cell Antigen Receptor Specificity CD8-Positive T-Lymphocytes Mice 0302 clinical medicine Tumor Microenvironment Recombinase T-cell receptor Breast RNA-Seq T Cells T Cell Receptor Recombination/Revision Machinery Tumor Microenvironment Cancer Aged 80 and over Mice Knockout Recombination Genetic Nuclear Proteins hemic and immune systems Middle Aged DNA-Binding Proteins 030220 oncology & carcinogenesis Female Single-Cell Analysis MutL Protein Homolog 1 Adult Immunology Receptors Antigen T-Cell T cells Breast Neoplasms chemical and pharmacologic phenomena Settore MED/08 - Anatomia Patologica Biology Recombination-activating gene 03 medical and health sciences Lymphocytes Tumor-Infiltrating Immune system Antigen DNA Nucleotidylexotransferase RAG2 Animals Humans Settore MED/05 - Patologia Clinica Aged Homeodomain Proteins Tumor microenvironment T-cell receptor Disease Models Animal Immunoediting Cancer research DNA Damage 030215 immunology

description

AbstractTumors undergo dynamic immunoediting as part of a process that balances immunologic sensing of emerging neoantigens and evasion from immune responses. Tumor-infiltrating lymphocytes (TIL) comprise heterogeneous subsets of peripheral T cells characterized by diverse functional differentiation states and dependence on T-cell receptor (TCR) specificity gained through recombination events during their development. We hypothesized that within the tumor microenvironment (TME), an antigenic milieu and immunologic interface, tumor-infiltrating peripheral T cells could reexpress key elements of the TCR recombination machinery, namely, Rag1 and Rag2 recombinases and Tdt polymerase, as a potential mechanism involved in the revision of TCR specificity. Using two syngeneic invasive breast cancer transplantable models, 4T1 and TS/A, we observed that Rag1, Rag2, and Dntt in situ mRNA expression characterized rare tumor-infiltrating T cells. In situ expression of the transcripts was increased in coisogenic Mlh1-deficient tumors, characterized by genomic overinstability, and was also modulated by PD-1 immune-checkpoint blockade. Through immunolocalization and mRNA hybridization analyses, we detected the presence of rare TDT+RAG1/2+ cells populating primary tumors and draining lymph nodes in human invasive breast cancer. Analysis of harmonized single-cell RNA-sequencing data sets of human cancers identified a very small fraction of tumor-associated T cells, characterized by the expression of recombination/revision machinery transcripts, which on pseudotemporal ordering corresponded to differentiated effector T cells. We offer thought-provoking evidence of a TIL microniche marked by rare transcripts involved in TCR shaping.

year	journal	country	edition	language
2021-01-01

10.1158/2326-6066.cir-20-0645 http://hdl.handle.net/2318/1792717