STIM1 and STIM2-mediated Ca(2+) influx regulates antitumour immunity by CD8(+) T cells.
Store-operated calcium entry (SOCE) through Ca(2+) release-activated Ca(2+) (CRAC) channels regulates the function of many immune cells. Patients with loss-of-function mutations in the CRAC channel genes ORAI1 or STIM1 are immunodeficient and are prone to develop virus-associated tumours. This and the reported role of Ca(2+) signals in cytotoxic lymphocyte function suggest that SOCE may be critical for tumour immune surveillance. Using conditional knock out mice lacking STIM1 and its homologue STIM2, we find that SOCE in CD8(+) T cells is required to prevent the engraftment of melanoma and colon carcinoma cells and to control tumour growth. SOCE is essential for the cytotoxic function of CTLs both in vivo and in vitro by regulating the degranulation of CTLs, their expression of Fas ligand and production of TNF-α and IFN-γ. Our results emphasize an important role of SOCE in antitumour immunity, which is significant given recent reports arguing in favour of CRAC channel inhibition for cancer therapy.
Department of Pathology and Cancer Institute, New York University School of Medicine, New York, NY, USA.
Carl
C
Weidinger
Patrick J
PJ
Shaw
Stefan
S
Feske
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000276:immunology*; D017422:Sequence Analysis, DNA; D015398:Signal Transduction; D000071737:Stromal Interaction Molecule 1; D000071738:Stromal Interaction Molecule 2; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D015220:Calcium Channels; D008562:Membrane Glycoproteins; C100757:Stim1 protein, mouse; C525024:Stim2 protein, mouse; D000071737:Stromal Interaction Molecule 1; D000071738:Stromal Interaction Molecule 2; D002118:Calcium
CTL; SOCE; STIM1; STIM2; tumour immunity