Prospective Immunophenotyping of CD8+ T Cells and Associated Clinical Outcomes of Patients With Oligometastatic Prostate Cancer Treated With Metastasis-Directed SBRT

Abstract

Purpose: This study examined the effects of metastasis-directed stereotactic body radiation therapy (mdSBRT) on CD8+ T-cell subpopulations and correlated post-mdSBRT immunophenotypic responses with clinical outcomes in patients with oligometastatic prostate cancer (OPCa).

Methods and materials: Peripheral blood mononuclear cells were prospectively isolated from 37 patients with OPCa (≤3 metastases) who were treated with mdSBRT. Immunophenotyping identified circulating CD8+ T-cell subpopulations, including tumor-reactive (TTR), effector memory, central memory (TCM), effector, and naïve T cells from samples collected before and after mdSBRT. Univariate Cox proportional hazards regression was used to assess whether changes in these T-cell subpopulations were potential risk factors for death and/or progression. The Kaplan-Meier method was used for survival. Cumulative incidence for progression and new distant metastasis weas estimated, considering death as a competing risk.

Results: Median follow-up was 39 months (interquartile range, 34-43). Overall survival at 3 years was 78.2%. Cumulative incidence for local progression and new distant metastasis at 3 years was 16.5% and 67.6%, respectively. Between baseline and day 14 after mdSBRT, an increase in the TCM cell subpopulation was associated with the risk of death (hazard ratio, 1.22 [95% confidence interval, 1.02-1.47]; P = .033), and an increase in the TTR cell subpopulation was protective against the risk of local progression (hazard ratio, 0.80 [95% confidence interval, 0.65-0.98]; P = .032).

Conclusions: An increase in the TTR cell subpopulation was protective against the risk of disease progression, and an increase in the TCM cell subpopulation was associated with the risk of death in patients with OPCa treated with mdSBRT. Disease control may be further improved by better understanding the CD8+ T-cell subpopulations and by enhancing their antitumor effect.

Trial registration: ClinicalTrials.gov NCT01777802.

Conflict of interest statement

Conflicts of interest: The authors declare no potential conflicts of interest.

Copyright © 2018 Elsevier Inc. All rights reserved.

Figures

FIGURE 1.. Survival and Cumulative Incidence Curves

Kaplan-Meier survival plot (A) and cumulative incidence curves with competing risk of death (B-D) showing clinical outcomes for the entire study group (left) and dichotomized by castrate-resistant status (right).

FIGURE 2.. Association between the Post-mdSBRT Immunophenotypic Responses in Circulating CD8+ T-cell Subpopulations and Clinical Outcomes

Forest plots demonstrating the association between changes in the relative percentage of circulating CD8+ T-cell subpopulations and clinical outcomes including (A) death, (B) any disease progression, local or distant, (C) new distant metastasis, and (D) local progression. All plots shown convey the results of immunophenotypic changes that occurred between baseline and day 14 after metastasis-directed stereotactic body radiation therapy. Hazard ratios are per 1 unit increase in the variable. TN (CD8+CCR7+CD45RA+), Naïve T-cell; TEF (CD8+CCR7-CD45RA+), Effector T-cell; TCM (CD8+CCR7+CD45RA-), Central Memory T-cell; TEM (CD8+CCR7-CD45RA-), Effector Memory T-cell; TTR (CD8+PD-1+CD11ahigh), Tumor-Reactive T-cell; CI, Confidence Interval.

FIGURE 3.. Changes in CD8+ T-cell subpopulations that correlate with significant clinical outcomes.

Graphs demonstrate the mean percentage change in (A) Tumor-Reactive (TTR) T-cells as a function of time at baseline before metastasis-directed SBRT and 1, 7 and 14 days after SBRT for patients that experienced local progression (blue), did not experience local progression (red), and all patients (green). (B) Mean percentage change in Central Memory (TCM) T-cells as a function of time at baseline before metastasis-directed SBRT and 1, 7, and 14 days after SBRT for patients that died (blue), remain alive (red), and all patients (green). (C) Mean percentage change in Tumor-Reactive (TTR) T-cells as a function of time at baseline before metastasis-directed SBRT and 1, 7, and 14 days after SBRT for patients that experienced any progression (blue), did not experience progression (red), and all patients (green).