Prospective Immunophenotyping of CD8+ T-cells and Associated Clinical Outcomes of Patients with Oligometastatic Prostate Cancer Treated with Metastasis-Directed Stereotactic Body Radiation Therapy

Abstract

To prospectively observe CD8+ T-cell immunophenotypic changes in prostate cancer (PCa) patients treated with metastasis-directed stereotactic body radiation therapy (mdSBRT) and correlate these phenotypic changes with clinical outcomes. We prospectively analyzed peripheral blood mononuclear cells (PBMCs) that were isolated – before and at multiple time points after mdSBRT – from 37 patients enrolled between January 2013 and October 2014 with recurrent oligometastatic PCa (≤3 extracranial sites). Immunophenotyping was performed on isolated PBMCs using flow cytometry to identify subpopulations of circulating CD8+ T-cells including Tumor-Reactive (TTR; PD-1+CD11ahigh), Effector Memory (TEM; CCR7-CD45RA-), Central Memory (TCM; CCR7+CD45RA-), Effector (TEF; CCR7-CD45RA+), and Naïve (TN; CCR7+CD45RA+) T-cells. Univariate Cox proportional hazards regression was used to assess whether changes in these T-cell subpopulations were potential risk factors for death and progression. Kaplan-Meier method was used for survival. Cumulative incidence for progression and new distant metastasis (NDM) was estimated considering death as a competing risk. Median follow-up was 39 months (IQR 34-43). Overall survival at 3 years was 78.2%. Cumulative incidence for local progression at 3 years was 16.5% and for NDM at 3 years was 67.6%. Androgen deprivation therapy (ADT) was given concurrently with mdSBRT vs. delayed until additional progression for 19 (51%) and 18 (49%) patients, respectively. Concurrent ADT was protective against the risk of NDM (HR 0.44; 95% CI 0.20-0.96; p=0.039). Median time to NDM was 28 (IQR 5-41) vs. 8 (IQR 4-12) months for concurrent vs. delayed ADT, respectively. Seven out of 7 (100%) patients that continue to remain progression-free received concurrent ADT with mdSBRT. An increase in the TCM cell subpopulation between baseline and day 14 after mdSBRT was associated with the risk of death (HR 1.22; 95% CI 1.02-1.47; p=0.033). An increase in the TTR cell subpopulation between baseline and day 14 was protective against the risk of local progression (HR 0.80; 95% CI 0.65-0.98; p=0.032). Relative increases ≥1% in the TTR cell subpopulation between baseline and day 14 were associated with a non-significant protective effect against the risk of any progression, distant or local (HR 0.42; 0.17-1.01; p=0.052). Prospective CD8+ T-cell immunophenotyping before and after mdSBRT in patients with oligometastatic PCa provided insight into clinical outcomes. An increase in the TCM cell subpopulation was associated with the risk of death. An increase in the TTR cell subpopulation was protective against the risk of local progression. Concurrent ADT with mdSBRT was protective against the risk of NDM. This is the first report to show that an increase in the TTR cell subpopulation after mdSBRT is associated with PCa disease control, and has implications for combining mdSBRT and adoptive cell transfer therapies. Supported by NCI R01 CA200551.