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Supplementary Table 4 from T Cells Expressing Receptor Recombination/Revision Machinery Are Detected in the Tumor Microenvironment and Expanded in Genomically Over-unstable Models

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posted on 2023-04-04, 01:01 authored by Gaia Morello, Valeria Cancila, Massimo La Rosa, Giovanni Germano, Daniele Lecis, Vito Amodio, Federica Zanardi, Fabio Iannelli, Daniele Greco, Laura La Paglia, Antonino Fiannaca, Alfonso M. Urso, Giulia Graziano, Francesco Ferrari, Serenella M. Pupa, Sabina Sangaletti, Claudia Chiodoni, Giancarlo Pruneri, Alberto Bardelli, Mario P. Colombo, Claudio Tripodo

Supplementary Table 4

Funding

Italian Foundation for Cancer Research

AIRC Accelerator Award

AIRC 5 per mille

AIRC-CRUK-FC AECC Accelerator Award

History

ARTICLE ABSTRACT

Tumors 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.

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