Tumor-induced impairment of TCR signaling results in compromised functionality of tumor-infiltrating regulatory T cells.
This study demonstrates, for the first time, that murine regulatory T (Treg) cells in the tumor microenvironment display both enhanced proliferation and reduced functionality. This enhanced proliferation, combined with decreased apoptosis, leads to an intratumoral accumulation of Treg cells with a unique phenotype: CD4(+)CD25(+)FoxP3(+)GITR(high)CD27(low)CD62L(-). The loss of functionality is associated with down-regulation of the TCR signaling complex, including IL-2-inducible T cell kinase. It is also demonstrated that tumor-infiltrating Treg cells have impaired TCR-mediated signaling and calcium influx. Based on these findings, this study supports the hypothesis that 1) tumor-infiltrating Treg cells lose functionality due to their diminished ability to become effectively activated and 2) intratumoral accumulation of Treg cells may compensate for the impaired functionality, thus maintaining immune tolerance to the tumor.
Lutsiak
M E Christine
ME
Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Tagaya
Yutaka
Y
Adams
Anthony J
AJ
Schlom
Jeffrey
J
Sabzevari
Helen
H
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D020013:Calcium Signaling / Q000276:immunology*; D049109:Cell Proliferation; D015536:Down-Regulation / Q000276:immunology; D005260:Female; D007108:Immune Tolerance; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000201:enzymology / Q000276:immunology*; D011505:Protein-Tyrosine Kinases / Q000276:immunology / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000201:enzymology / Q000276:immunology*
D011948:Receptors, Antigen, T-Cell; D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase