Back to Search
Start Over
T Cells Expressing Receptor Recombination/Revision Machinery Are Detected in the Tumor Microenvironment and Expanded in Genomically Over-unstable Models.
- Source :
-
Cancer immunology research [Cancer Immunol Res] 2021 Jul; Vol. 9 (7), pp. 825-837. Date of Electronic Publication: 2021 May 03. - Publication Year :
- 2021
-
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 <superscript>+</superscript> RAG1/2 <superscript>+</superscript> 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.<br /> (©2021 American Association for Cancer Research.)
- Subjects :
- Adult
Aged
Aged, 80 and over
Animals
Breast immunology
Breast pathology
Breast Neoplasms genetics
Breast Neoplasms pathology
CD8-Positive T-Lymphocytes metabolism
DNA Damage immunology
DNA Nucleotidylexotransferase genetics
DNA Nucleotidylexotransferase metabolism
DNA-Binding Proteins metabolism
Datasets as Topic
Disease Models, Animal
Female
Homeodomain Proteins metabolism
Humans
Lymphocytes, Tumor-Infiltrating metabolism
Mice
Mice, Knockout
Middle Aged
MutL Protein Homolog 1 genetics
MutL Protein Homolog 1 metabolism
Nuclear Proteins metabolism
RNA-Seq
Receptors, Antigen, T-Cell
Single-Cell Analysis
Tumor Microenvironment genetics
Tumor Microenvironment immunology
Breast Neoplasms immunology
CD8-Positive T-Lymphocytes immunology
Lymphocytes, Tumor-Infiltrating immunology
Recombination, Genetic immunology
T-Cell Antigen Receptor Specificity genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2326-6074
- Volume :
- 9
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Cancer immunology research
- Publication Type :
- Academic Journal
- Accession number :
- 33941587
- Full Text :
- https://doi.org/10.1158/2326-6066.CIR-20-0645