Association between immunosuppressive cytokines and PSA progression in biochemically recurrent prostate cancer treated with intermittent hormonal therapy

Abstract

Background: Immunosuppressive cytokines have the potential to promote prostate cancer progression. Assessing their longitudinal changes may implicate mechanisms of progression, treatment resistance, and suggest new therapeutic targets.

Methods: Thirty-seven men with biochemically recurrent (BCR) prostate cancer who received 6 months of androgen deprivation therapy (ADT) and were monitored until the time to prostate-specific antigen progression (TTPP) were identified from a completed phase III trial (NCT00020085). Serum samples were archived at baseline, 3 months after ADT, and at TTPP. Cytokine concentrations were quantified using a 36-parameter electrochemiluminescence assay. The Wilcoxon signed-rank sum test was used to compare observations between time points. Kaplan-Meier analysis was used to calculate TTPP dichotomized by cytokine values above or below the median. Pearson's rank correlation coefficient was used to compare continuous variables.

Results: Median TTPP was 399 days (range, 114-1641). Median prostate-specific antigen (PSA) at baseline and progression were 8.5 and 5.3 ng/mL, respectively. Twenty-three patients (62%) achieved undetectable PSA with ADT. Castrate levels of testosterone (<50 ng/dL) after 3 months of ADT occurred in 35 patients (95%). TNF-α (P = .002), IL-23 (P = .002), and CXCL10 (P = .001) significantly increased from baseline to post ADT. Certain cytokines correlated longitudinally: TNF-α correlated with IL-23 (r = .72; P < .001) and IL-8 (r = .59; P < .001) from baseline to post ADT and to PSA progression. Neutrophil-to-lymphocyte ratio correlated with IL-27 (r = .57; P < .001) and MIP-3α (r = .56; P < .001). Patients with a detectable PSA after ADT had elevated levels of IL-6 (P = .049) and IL-8 (P = .013) at PSA progression as compared with those with an undetectable PSA. There was a trend toward shorter TTPP in patients with TNF-α levels above the median (P = .042).

Conclusions: Several innate cytokines were associated with biochemically recurrent prostate cancer.

Keywords: IL-23; IL-8; TNF-α; biochemical recurrence.

Figure 1.. ADT is associated with changes in cytokine levels.

Cytokine concentrations at baseline, three months after ADT, and at time of PSA progression in all 37 analyzed patients. Horizontal lines represent the median, boxes the interquartile range (IQR), and whiskers the upper and lower quartiles. Wilcoxon signed-rank sum test was used to compare paired observations between different time points. Horizontal bars denote statistical significance between time points (P < 0.05 *, < 0.01 **). Outliers represented by black dots.

Figure 2.. Innate immunosuppressive cytokines correlate longitudinally.

Correlation matrices of serum cytokine concentrations between time points, including A) from baseline to three months after ADT, B) from three months after ADT to time of PSA progression, and C) from baseline to time of PSA progression. Color intensity and the size of the circle are proportional to the strength of the correlation coefficient. Blue represents a positive correlation with darker colors approaching r = 1 and red represents a negative correlation with darker colors approaching r = −1. Only correlations with significance of ≤ 0.05 are shown. Empty spaces reflect correlations with p-value > 0.05. Clustering analysis was performed using H clust for 3 clusters. Pearson’s rank correlation coefficients were calculated and controlled for multiple comparisons using false discovery rates.

Figure 3.. Lack of PSA Response to ADT is associated with elevations in immunosuppressive cytokines.

Violin plots depicting the frequency of distribution for IL-8, IL-6, IL-23, and TNF-α concentrations at baseline, three months after ADT, and at time of PSA progression in 37 patients dichotomized by PSA response after three months of ADT (undetectable, <0.2 ng/mL; detectable, > 0.2 ng/mL). Solid horizontal lines represent the median, dashed lines the upper and lower quartiles, width of the violin plot represents the proportion of the data located there. Wilcoxon signed-rank sum test was used to compare observations between different groups. Horizontal bars denote statistical significance between groups (P < 0.05 *).

Figure 4.. Elevated levels of immunosuppressive cytokines at baseline associated with shorter time to PSA progression.

Kaplan-Meier analysis of time to PSA progression-free survival in men with BCR treated with 6 months of ADT (n = 37) dichotomized by above or below median of TNF-α, IL-7, and VEGF concentrations at baseline.