Resistance of CD45RA- T cells to apoptosis and functional impairment, and activation of tumor-antigen specific T cells during radiation therapy of prostate cancer.
The effect of radiation therapy (RT) to the pelvis on circulating T cells was studied in prostate cancer (PCa) patients to provide a baseline for a more informed design of combination radioimmunotherapy. Peripheral blood samples taken from 12 PCa patients with locally advanced tumor before, during, and after hypofractionated RT were analyzed for T cell phenotype and function. There was significantly more loss of naive and early memory compared with more differentiated T cells during RT. The proportions of annexin-V(+) and Fas-expressing T cells were elevated in patients during RT and in PBMC irradiated in vitro (< or = 5.0 Gy), with preferential increases in CD45RA(+) T cells. The baseline level of apoptosis of CD45RA(-) T cells increased > 2-fold in the presence of an IkappaB-kinase inhibitor, indicating a protective effect via this pathway. T cell proliferation was impaired during RT with IL-2-dependent recovery post-RT. Recall T cell responses to common viral Ags, measured by IFN-gamma production, were little affected by RT. In vitro irradiation of healthy donor PBMCs resulted in a significantly increased frequency of responding T cells, due at least partly to the preferential elimination of CD45RA(+) T cells. Most importantly, antitumor CD4(+) and CD8(+) T cell responses were detectable after, but not before or during RT. The results indicate that generating tumor-specific T cell responses before RT and boosting their activity post-RT are ways likely to amplify the frequency and function of antitumor T cells, with implications for scheduling immunotherapy in PCa.
Tabi
Zsuzsanna
Z
Department of Pharmacology, Radiology and Oncology, School of Medicine, Cardiff University, Cancer Research Wales Research Laboratories, Velindre Cancer Centre, Whitchurch, Cardiff, CF14 2TL, UK. zsuzsanna.tabi@wales.nhs.uk
Spary
Lisa K
LK
Coleman
Sharon
S
Clayton
Aled
A
Mason
Malcolm D
MD
Staffurth
John
J
D000368:Aged; D000595:Amino Acid Sequence; D000951:Antigens, Neoplasm / Q000276:immunology*; D017209:Apoptosis / Q000276:immunology* / Q000528:radiation effects; D049109:Cell Proliferation / Q000528:radiation effects; D002478:Cells, Cultured; D005434:Flow Cytometry; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D007156:Immunologic Memory / Q000276:immunology; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000276:immunology / Q000378:metabolism; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D011471:Prostatic Neoplasms / Q000097:blood / Q000276:immunology* / Q000532:radiotherapy; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000528:radiation effects; D019014:fas Receptor / Q000276:immunology / Q000378:metabolism
D000951:Antigens, Neoplasm; D019014:fas Receptor; D007371:Interferon-gamma; D051550:I-kappa B Kinase; D017493:Leukocyte Common Antigens