Although much is known about the initiation of immune responses, much less is known about what controls the effector phase. CD8+ T cell responses are believed to be programmed in lymph nodes during priming without any further contribution by dendritic cells (DCs) and Ag. In this study, we report the requirement for DCs, Ag, and CD28 costimulation during the effector phase of the CD8+ T cell response. Depleting DCs or blocking CD28 after day 6 of primary influenza A virus infection decreases the virus-specific CD8+ T cell response by inducing apoptosis, and this results in decreased viral clearance. Furthermore, effector CD8+ T cells adoptively transferred during the effector phase fail to expand without DC, CD28 costimulation, and cognate Ag. The absence of costimulation also leads to reduced survival of virus-specific effector cells as they undergo apoptosis mediated by the proapoptotic molecule Bim. Finally, IL-2 treatment restored the effector response in the absence of CD28 costimulation. Thus, in contrast to naive CD8+ T cells, which undergo an initial Ag-independent proliferation, effector CD8+ T cells expanding in the lungs during the effector phase require Ag, CD28 costimulation, and DCs for survival and expansion. These requirements would greatly impair effector responses against viruses and tumors that are known to inhibit DC maturation and in chronic infections and aging where CD28−/− CD8+ T cells accumulate.

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ObjectiveThe low alpha/beta ratio of prostate cancer suggests that hypofractionated schemes of dose-escalated radiotherapy should be advantageous. We report our experience using stereotactic body radiation therapy (SBRT) for the primary treatment of prostate cancer to assess efficacy and toxicity.MethodsFrom 2007 to 2010, 70 patients (51 % low risk, 31 % intermediate risk, and 17 % high risk) with localized prostate cancer were treated with SBRT using the CyberKnife system. One-third of patients received androgen deprivation therapy. Doses of 37.5 Gy (n = 29), 36.25 Gy (n = 36), and 35 Gy (n = 5) were administered in five fractions and analyzed as high dose (37.5 Gy) vs. low dose (36.25 and 35 Gy).ResultsAt a median 27 and 37 months follow-up, the low and high dose groups' median PSA nadir to date was 0.3 and 0.2 ng/ml, respectively. The 3-year freedom from biochemical failure (FFBF) was 100 %, 95.0 % and 77.1 % for the low-, intermediate- and high-risk patients. A dose response was observed in intermediate- and high-risk patients with 72 % vs. 100 % 3-year FFBF for the low and high dose groups, respectively (p = 0.0363). Grade III genitourinary toxicities included 4 % acute and 3 % late (all high dose). Potency was preserved in 83 % of hormone naïve patients.ConclusionCyberKnife dose escalated SBRT for low-, intermediate- and high-risk prostate cancer exhibits favorable efficacy with acceptable toxicity.

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