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 (≤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 IκB-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-γ 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.