Apoptosis of CD4(+)CD25(high) T cells in response to Sirolimus requires activation of T cell receptor and is modulated by IL-2.
Targeted molecular therapies inhibit proliferation and survival of cancer cells but may also affect immune cells. We have evaluated the effects of Sirolimus and Sorafenib on proliferation and survival of lymphoid cell subsets. Both drugs were cytotoxic to CD4(+)CD25(high) T cells, and were growth inhibitory for CD4(+) and CD8(+) T cells. Cytotoxicity depended on CD3/CD28 stimulation and was detectable within 12 h, with 80-90% of CD4(+)CD25(high) cells killed by 72 h. Cell death was due to apoptosis, based on Annexin V and 7AAD staining. Addition of IL-2 prevented the apoptotic response to Sirolimus, potentially accounting for reports that Sirolimus can enhance proliferation of CD4(+)CD25(high) cells. These results predict that Sirolimus or Sorafenib would reduce CD4(+)CD25(high) cells if administered prior to antigenic stimulation in an immunotherapy protocol. However, administration of IL-2 protects CD4(+)CD25(high) T cells from cytotoxic effects of Sirolimus, a response that may be considered in design of therapeutic protocols.
Division of Surgical Oncology, Department of Surgery, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
Kerrington R
KR
Molhoek
Chantel C
CC
McSkimming
Walter C
WC
Olson
David L
DL
Brautigan
Craig L
CL
Slingluff
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001557:Benzenesulfonates / Q000494:pharmacology; D018106:CD28 Antigens / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005434:Flow Cytometry; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007376:Interleukin-2 / Q000494:pharmacology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000187:drug effects; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D020123:Sirolimus / Q000494:pharmacology*; D000077157:Sorafenib; D048490:raf Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D001557:Benzenesulfonates; D018106:CD28 Antigens; D017252:CD3 Complex; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011948:Receptors, Antigen, T-Cell; D009536:Niacinamide; D000077157:Sorafenib; D048490:raf Kinases; D020123:Sirolimus