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 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.
Morello G., Cancila V., La Rosa M., Germano G., Lecis D., Amodio V., et al. (2021). T cells expressing receptor recombination/revision machinery are detected in the tumor microenvironment and expanded in genomically over-unstable models. CANCER IMMUNOLOGY RESEARCH, 9(7), 825-837 [10.1158/2326-6066.CIR-20-0645].
Data di pubblicazione: | 2021 | |
Titolo: | T cells expressing receptor recombination/revision machinery are detected in the tumor microenvironment and expanded in genomically over-unstable models | |
Autori: | MORELLO, Gaia (Primo) TRIPODO, Claudio (Ultimo) (Corresponding) | |
Citazione: | Morello G., Cancila V., La Rosa M., Germano G., Lecis D., Amodio V., et al. (2021). T cells expressing receptor recombination/revision machinery are detected in the tumor microenvironment and expanded in genomically over-unstable models. CANCER IMMUNOLOGY RESEARCH, 9(7), 825-837 [10.1158/2326-6066.CIR-20-0645]. | |
Rivista: | ||
Digital Object Identifier (DOI): | http://dx.doi.org/10.1158/2326-6066.CIR-20-0645 | |
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 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. | |
Settore Scientifico Disciplinare: | Settore MED/08 - Anatomia Patologica Settore MED/05 - Patologia Clinica | |
Appare nelle tipologie: | 1.01 Articolo in rivista |
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