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VALERIA CANCILA

T cells expressing receptor recombination/revision machinery are detected in the tumor microenvironment and expanded in genomically over-unstable models

  • Autori: Morello G.; Cancila V.; La Rosa M.; Germano G.; Lecis D.; Amodio V.; Zanardi F.; Iannelli F.; Greco D.; La Paglia L.; Fiannaca A.; Urso A.M.; Graziano G.; Ferrari F.; Pupa S.M.; Sangaletti S.; Chiodoni C.; Pruneri G.; Bardelli A.; Colombo M.P.; Tripodo C.
  • Anno di pubblicazione: 2021
  • Tipologia: Articolo in rivista
  • OA Link: http://hdl.handle.net/10447/607354

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 situmRNA expression characterized rare tumor-infiltrating T cells. In situ expression of the transcripts was increased in coisogenic Mlh1deficient 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.